Hexahydro-trans- and tetrahydropyridoindole neuroleptic agents

ABSTRACT

Derivatives of 2,3,4,5-tetrahydro-1H-pyrido[4,3-b]-indole and of (+)enantiomeric, mixtures of (+) and (-)enantiomeric or (±)racemic 2,3,4,4a,5,9b-hexahydro-4a,9b-trans-1H-pyrido[4,3-b]indole, substituted at the 5-position with an aryl group and at the 2-position with a carbonylaminoalkyl group or an aminoalkyl group, are neuroleptic agents useful in the treatment of certain psychoses and neuroses.

CROSS REFERENCE TO RELATED APPLICATIONS

This application is a division of copending application Ser. No.259,569, filed Jan. 16, 1981 now U.S. Pat. No. 4,337,250 which is acontinuation-in-part of pending application Ser. No. 182,177 filed Aug.28, 1980, now abandoned, which is a division of application Ser. No.061,573 filed July 30, 1979 now U.S. Pat. No. 4,252,811.

BACKGROUND OF THE INVENTION

The successful treatment of schizophrenic behavior using antipsychotictranquilizers such as chlorpromazine has stimulated research to findother neuroleptic agents having improved biological profiles. One suchclass of compounds is the2,3,4,4a,5,9a-hexahydro-1H-pyrido[4,3-b]-indoles and the2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indoles. The basic ring structuresare ##STR1## The stereochemistry at positions 4a and 9b in the hexahydroseries can be cis or trans, each of which can exist in racemic(±) orenantomeric(+ or -) forms. Examples of hexahydro- andtetrahydro-pyridoindoles that are useful as tranquilizers, neurolepticagents, analgesics, sedatives, muscle relaxants and hypotensive agentsare given in the following U.S. Patents: U.S. Pat. No. 3,687,961; U.S.Pat. No. 3,983,239; U.S. Pat. No. 3,991,199; U.S. Pat. No. 4,001,263;U.S. Pat. No. 4,141,980; and U.S. Pat. No. 4,224,329.

Potent neuroleptic activity has now been discovered for novel2,3,4,4a,5,9b-hexahydro-4a,9b-trans-1H-pyrido[4,3-b]indoles and2,3,4,5-tetrahydro-1H-pyrido[4,3-b]inoles substituted at the 5-positionwith an aryl group and the 2-position with an aminoalkyl group or acarbonylaminoalkyl group (the carbonyl group either further substitutedwith a radical such as hydrogen, alkyl, aryl, aralkyl or alkoxy; orbridged to the amine by a diradical such as alkano[--(CH₂)_(i) --,wherein i is 3 to 5] or a 3-6 atom chain containing various combinationsof carbonyl, alkano, alkeno--(CH═CH--), o-benzeno ##STR2## imino, sulfuror oxygen.

SUMMARY OF THE INVENTION

The neuroleptic agents of the present invention are (+)enantiomeric, amixture of (+) and (-)enantiomeric or (±)racemic2,3,4,4a,5,9b-hexahydro-4a,9b-trans-1H-pyrido[4,3-b]indole derivativesof formulae: ##STR3## wherein k is an integer of value 1 or 2;

n is an integer of value 2 to 9;

p is 0 or 1;

X and Y are each independently H, F, Cl, Br, OCH₃, CH₃ or CH₂ CH₃ ;

A is methano(--CH₂ --), ethano(--CH₂ CH₂ --), propano (--CH₂ CH₂ CH₂--), etheno(--CH═CH--), o-benzeno ##STR4## or a mono or disubstitutedform of o-benzeno, the monosubstituent and each of the disubstituentsbeing independently F, Cl, Br, OCH₃, CH₃ or CH₂ CH₃ ;

with the proviso that when A is methano, p is 1, thus excluding4-membered rings which are not within the scope of the presentinvention;

Z is methano, oxygen, sulfur or NR² ; and

R² is H, (C₁ -C₅)alkyl, phenyl, benzyl or a ring mono- or disubstitutedform of phenyl or benzyl, the monosubstituent and each of thedisubstituents being independently F, Cl, Br, OCH₃, CH₃ or CH₂ CH₃ ;##STR5## wherein ##STR6## Z¹ is methano or NR² ; k, n, X, Y, p and R²are as defined above;

A¹ is oxygen, NR³, methano, ethano, etheno, o-benzeno, or a mono- ordisubstituted form of o-benzeno, the mono and each of the disubstituentsbeing independently F, Cl, Br, OCH₃, CH₃ or CH₂ CH₃ ; and

R³ is independently a value of R² as defined above;

with the proviso that when A¹ is methano, oxygen or NR³, p is 1, againto exclude 4-member rings as outside the scope of the present invention;##STR7## wherein ##STR8## A² and Z² when taken together and A³ and Z³when taken together are ethano, propano, etheno, o-benzeno or a mono- ordisubstituted form of o-benzeno, the mono and each of the disubstituentsbeing independently F, Cl, Br, OCH₃, CH₃ or CH₂ CH₃ ;

A³ when taken separately is methano, ethano, etheno, o-benzeno or amono- or disubstituted form of o-benzeno, the monosubstituents and eachof the disubstituents being independently F, Cl, Br, OCH₃, CH₃ or CH₂CH₃ ;

Z³ when taken separately is oxygen, sulfur or NR² ; and k, n, X, Y andR² are as defined above; ##STR9## wherein k, X and Y are as definedabove;

m is an integer of value 1 to 6; and

R⁴ is H, (C₁ -C₅)alkyl, phenyl, benzyl, (C₁ -C₈)alkanoyl, (C₁-C₈)alkoxycarbonyl, benzoyl, phenylacetyl, (C₁ -C₈)alkylsulfonyl,phenylsulfonyl, or a ring mono- or disubstituted form of phenyl, benzyl,benzoyl, phenylacetyl or phenylsulfonyl, the monosubstituent and each ofthe disubstituents being independently F, Cl, Br, OCH₃, CH₃ or CH₂ CH₃ ;and 2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indoles of the formula ##STR10##wherein k, n, X and Y are as defined above;

R⁵ taken separately is hydrogen;

R⁶ taken separately is (C₁ -C₈)alkanoyl or (C₁ -C₈)alkoxycarbonyl; and

R⁵ and R⁶ taken together are ##STR11## wherein r is an integer of value3 to 5.

Also encompassed by the present invention are the pharmaceuticallyacceptable salts of the compounds defined above, pharmaceuticalcompositions of these compounds and a method of treating psychoses andneuroses in patients requiring major tranquilization which comprisesadministering to the patient by the oral or parenteral (intravenous,intramuscular or subcutaneous) route an effective amount of one of thesecompounds, alone or as a component of a pharmaceutical composition.

In all cases, the preferred compounds have the values: X is F, k is 1; Yis F (substituted at the para position) and n is 3 to 6 or m is 2 to 4.In the cases of the2,3,4,4a,5,9b-hexahydro-4a,9b-trans-1H-pyrido[4,3-b]indoles of theformulae (I) through (IV), the preferred compounds are the derivativesof either the racemic or more particularly of the (+)enantiomeric form.

Furthermore, the most preferred compounds of the formula (I) are thosewherein A is ethano; within the subgroup preferred compounds have p as 1and Z as methylene, or p as 0 and Z as oxygen. The preferred compoundsof the formula (II) have p as 1 with A¹ as methano and Z¹ as NR² (thepreferred values of R² in this subgroup are H and benzyl) or p as 0 withA¹ as o-benzeno. The preferred compounds of the formula (III) have asthe terminal group of the sidechain ##STR12## The most preferredcompounds of the structure (IV) have R⁴ as alkanoyl, alkoxycarbonyl,benzoyl or phenylacetyl; most highly preferred in this series are thosecompounds wherein R⁴ is acetyl. The most preferred compounds of thestructure (V) have R⁵ as hydrogen and R⁶ as acetyl or carbethoxy, or R⁵and R⁶ taken together as

Exemplary of the side chain terminal groups of the formula (I) are:##STR13##

Exemplary of the sidechain terminal groups of the formula (II) are:##STR14##

Exemplary of the sidechain terminal groups of the formula III are:##STR15##

DETAILED DESCRIPTION OF THE INVENTION

The compounds of the present invention are readily prepared by methodswhich are detailed in the following paragraphs. For purposes ofdiscussion, the instant2,3,4,4a,5,9b-hexahydro-4a,9b-trans-1H-pyrido[4,3-b]-indole and2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole nuclei, ##STR16## wherein k, Xand Y are as defined above, will be referred to, respectfully, as R andR", or generically as R'.

Compounds of the present invention can be regarded as synthesizable fromthree synthons, viz.,

(a) (±)RH, (+)RH, or R"H;

(b) an alpha, omega-disubstituted straight chain alkane (or alkaneprecursor); and

(c) a side chain terminal group, or terminal group precursor.

Synthesis of 2-piperidon-1-yl derivatives [formula I, p=1, Z=methano,A=ethano; formula V, R⁵ and R⁶ are taken together as (CH₂)₃ CO]illustrate the basic methods of approach which are applied.

Method A: (a)+(b)(c)→(a)(b)(c) ##STR17## wherein n and R' are as definedabove and D represents a displaceable group (Cl, Br, I, CH₃ SO₂ O,etc.). This nucleophilic displacement reaction is carried out in areaction inert solvent, such as a lower aliphatic ketone (e.g., acetone,2-butanone, 3-methyl-2-butanone, 3-methyl-2-pentanone), a lower alkanol(e.g., ethanol, 2-propanol), or a lower aliphatic amide (e.g.,dimethylformamide, dimethyl acetamide). The pyridoindole (RH, R"H) ispreferably maintained in the form of the much more reactive free base bythe addition of at least one equivalent of a base such as sodiumcarbonate to the reaction mixture. When D is other than I, iodide ioncan be added to enhance the reaction rate, if desired. Temperature isnot critical, the temperature usually being elevated (e.g., 50°-150° C.)to enhance the rate of reaction, but not so high as to cause undesirablelevels of thermal degradation of the products and/or reactants.

The pyrido[4,3-b]indoles required for these syntheses and the furthersyntheses detailed below are available by the methods of U.S. Pat. Nos.3,687,961; 3,983,239; 3,991,199; 4,001,263; 4,141,980 and 4,224,329.

The piperidone derivatives are readily available by reaction of theanion of 2-piperidone with a disubstituted alkane, D(CH₂)_(n) D, whereinD and n are as defined above and the D groups can be the same ordifferent. Bis-displacement is minimized by using excess D(CH₂)_(n) Dand/or by one group being more readily displaceable [e.g., Cl(CH₂)_(n)Br].

Reaction conditions (solvent and temperature) are generally as describedabove, except that protic solvents (e.g., alcohols), which are moreacidic than 2-piperidone, are avoided.

The same approach is broadly available for the synthesis of many othercompounds of the present invention. For example, those compounds whereinthe sidechain terminus is alkanoylamino, alkoxycarbonylamino, (Ib) to(Ij), (IIa) to (IIc), (IIIa) to (IIIf), or N-substituted variantsthereof. In other cases, for example, those compounds wherein thesidechain terminus is piperazino or of the formula (IId)-(IIh), the sameapproach is just as applicable when equally reactive or more reactivenitrogen atoms are already substituted, e.g., ##STR18## If thesubstituent is a group such as benzyl, the substituent can be removed byhydrogenolysis affording a synthesis of those compounds wherein theterminus is unsubstituted piperazino, or (IId) to (IIh), e.g., ##STR19##Method B: (a)(b)+(c)→(a)(b)(c) ##STR20## wherein R', n and D are asdefined above. This nucleophilic displacement is carried out usingsubstantically equivalent quantities of the reactants, otherwise underconditions as described above for the synthesis of ##STR21##

While the substituted pyrido[4,3-b]indoles are potentially available bya number of routes, the preferred route is: ##STR22##

The piperidone anion is generally formed in situ by reaction of thepiperidone with sodium hydride.

This approach is also broadly applicable to the synthesis of othercompounds of this invention, applying the principles enunciated in thepreceding section, e.g., ##STR23## Method C: (a)(b')(c)→(a)(b)(c)##STR24## wherein R and n are as defined above, and x and y are each 1or greater and x+y-2=n. These are hydrogenation reactions, carried outin an inert solvent under a hydrogen atmosphere in the presence of ahydrogenation catalyst, preferably a noble metal catalyst includingplatinum, palladium, rhodium and ruthenium, either of the supported ornon-supported type, as well as the known catalytic compounds thereofsuch as the oxides, chlorides, etc. Specific examples of suitablecatalysts are 5% palladium on carbon, 5% palladium on barium carbonate,5% rhodium on carbon, rhodium chloride, platinum oxide and 5% rutheniumon carbon. The temperature and pressure of the hydrogenation are notcritical, being generally carried out in a temperature range of 10°-90°C., conveniently 20°-50° C., at a pressure ranging from subatmosphericto 100 atmospheres, or more. A convenient operating pressure is 2-3atmospheres.

The starting materials required for these syntheses are generallyavailable by following method A above, but substituting an unsaturatedcompound for D(CH₂)_(n) D, e.g., ##STR25## The first stage nucleophilicdisplacement reaction is carried out under conditions described above.The second stage formaldehyde bridging of the acetylene to RH, iscarried out in a reaction inert solvent (a lower alkanol is well-suited)employing the free base form of RH, an equivalent of formaldehyde(conveniently as a 30% aqueous solution) and an equivalent of theacetylene in the presence of cuprous chloride as catalyst. Temperatureis not critical (e.g., 0°-50° C.), the reaction being convenientlycarried out at ambient temperature (20°-25° C.).

This approach is further available for the synthesis of many othercompounds of the present invention, when the terminus is free of groupswhich are subject to significant hydrogenation side-reaction under theconditions employed for hydrogenation of the unsaturation. In the caseof benzyl protecting groups, these can generally be removed in the samereaction as reduction of an unsaturated group, e.g., ##STR26##

When the terminus is free of carbonyl, hydride reduction of amideprecursors is a further viable route to compounds of the presentinvention, e.g., ##STR27## A further variation is to alternatively orsimultaneously reduce a different terminal amide group, e.g., ##STR28##

These hydride reductions are conveniently carried out with excesslithium aluminum hydride (two equivalents are required for each amidefunction) in an ether solvent (e.g., diethyl ether, tetrahydrofuran,dioxane) in the temperature range 0°-50° C. Alternatively, such amidesare reduced with diborane or aluminum hydride in the same type ofsolvent, or reacted with triethyloxonium fluoroborate (e.g., inmethylene chloride at 20°-30° C.) and then reduced with sodiumborohydride in a lower alkanol (e.g., ethanol) at 0°-25° C.

It will be noted that the approach of Method C, as detailed above, hasparticular value in the synthesis of the hexahydropyrido[4,3-b]indoles,specified as RH, since the tetrahydro compounds (R"H) have a double bondwhich can complicate hydrogenation of an olefin. However, when theterminus of a tetrahydro compound is a precursor amine, then the abovelithium aluminum hydride reduction of amide or nitrile is well suited,e.g., ##STR29## Diborane is, of course, not employed unless simultaneousconversion of tetrahydro to hexahydropyrido[4,3-b]indole is desired.

Method D: (a)(b)(c')→(a)(b)(c) ##STR30## wherein n, R' and D are asdefined above and R⁷ is (C₁ -C₅)alkyl. The nucleophilic displacement ofD is carried out under conditions detailed above. The anion can bepreformed or formed in situ with a strong base such as sodium hydride.The intermediate is conveniently derived by acylation of amine:##STR31## The intermediate amide need not be isolated, but can be formedin situ and then converted to the anion. The acylation is carried outunder mild conditions (e.g., -25° to 35° C.), usually in a reactioninert solvent in the presence of at least one equivalent of inorganicbase or of tert-amine (e.g., triethylamine, N-methylmorpholine).

The alternative process, cyclization of the amino ester precursor, isaccomplished by mere heating of the free base form of the amino ester ina reaction inert solvent, conveniently an aromatic hydrocarbon such asbenzene, toluene or xylene. Temperature is not critical (e.g., 80°-150°C., preferably 100°-125° C.) so that the reaction proceeds at areasonable rate, but thermal degradation is minimized. The preferredvalue of R⁷ is methyl, since cyclization occurs most rapidly at thelowest possible temperatures. The amino esters are conveniently preparedby alkylation of amine: ##STR32##

In modified form, the reactions described immediately above can beapplied to the preparation of other compounds of the present invention,e.g., ##STR33##

In further modified form the basic approach of Method D is broadlyapplicable to the synthesis of the compounds of the present invention,that is, to build up the side chain terminus from suitable precursor,e.g., ##STR34## wherein A⁴ is oxygen or NR³ and n, R' and R³ are asdefined above.

The pharmaceutically acceptable salts of the derivatives can be preparedby reaction with either about 1 molar equivalent or about 2 molesequivalents of an organic or mineral acid in either aqueous ornonaqueous solution. Since the compounds of the present invention aregenerally dibasic, either mono salts or bis salts are thereby formed,depending upon the molar equivalent of acid. Those compounds which aretribasic can, of course, form a tris salt, in which case three molarequivalents of acid can be used. Suitable salt forming acids includehydrochloric, hydrobromic, hydroiodic, sulfuric, phosphoric,methanesulfonic, p-toluenesulfonic, lactic, citric, tartaric, succinic,maleic and gluconic acids. The salt can be isolated by removal of thesolvent in vacuo or in an appropriate case, by precipitation.

The derivatives are useful as neuroleptic agents in the treatment ofmental disorders and illnesses including schizophrenia, psychoses andneuroses. Symptoms requiring such treatment include anxiety, aggression,agitation, depression, hallucinations, tension and emotional or socialwithdrawal. In general, the derivatives exhibit major tranquilizingactivity but have fewer side effects than the drugs presently in use.

The derivatives can be formulated in a variety of pharmaceuticalpreparations which contain the derivative alone or in combination withpharmaceutical carriers such as inert solid diluents, aqueous solutionsor various non-toxic, organic solvents and in dosage forms such asgelatin capsules, tablets, powders, lozenges, syrups, injectablesolutions and the like. Such carriers include water, ethanol, gelatins,lactose, starches, vegetable oils, petroleum jelly, gums, glycols, talc,benzoyl alcohols, and other known carriers for medicaments. If desired,these pharmaceutical preparations can contain additional material suchas preserving agents, wetting agents, stabilizing agents, lubricatingagents, absorption agents, buffering agents and isotonic agents.

The derivatives are administered to a patient in need of treatment by avariety of conventional routes of administration such as oral,intravenous, intramuscular or subcutaneous. In general, small doses willbe administered initially with a gradual increase in the dose until theoptimum level is determined. However, as with any drug the particulardose, formulation and route of administration will vary with the age,weight and response of the particular patient and will depend upon thejudgment of his attending physician.

In the usual course of treatment a dose of a derivative of approximately0.1 mg per day to 100 mg per day will provide effective treatment forthe human patient. When the derivative has a prolonged effect, the dosecan be administered less frequently, such as every other day or in 1 or2 divided doses per week.

The tranquilizing activity of the derivatives may be determined usingthe well known standard procedure-antagonism of amphetamine-inducedsymptoms in rats. This method has excellent correlation with humanefficacy and is taught by A. Weissman, et al., J. Pharmacol. Exp. Therm.151, p. 339 (1966) and by Quinton, et al., Nature 200, p. 178, (1963),and more particularly by Harbert et al., Molecular Pharmacology 17, pp.38-41 (1980). In detail neuroleptic effects in vivo were estimated bythe blockade of amphetamine stereotypy. Rates were placed individuallyin covered plastic compartments; after a brief period of acclimation inthe cages the rats in groups of five were treated intraperitoneally withthe test compound at doses separated by 0.5 log units (i.e., . . . 1,3.2, 10, 32, . . . mg/kg). They were subsequently treated 1, 5, and 24hr later with d-amphetamine sulfate, 5 mg/kg ip. One hour after eachamphetamine challenge, each rat was assessed for its most characteristiccage movement behavior on a 6-point scale [Weissman et al., J.Pharmacol. Exp. Ther. 151, pp. 339-352 (1966)]. These ratings representincreasing degrees of drug effect [Quinton and Halliwell, Nature(London) 200, pp. 178-179 (1963)] and the time of rating chosencoincides with the peak effect of amphetamine [Weissman,Psychopharmacologia 12, pp. 142-157 (1968)]. Scores were dichotomized(cf. Weissman et al., loc. cit.), and approximate ED₅₀ 's weredetermined, based on the quantal data. Doses are expressed in terms ofthe hydrochloride salts. As illustrated by the results tabulated inTable I, this method shows that the compounds of the present inventionhave excellent tranquilizing activity compared to the standard testdrug, chlorpromazine.

So called "intrinsic" tranquilizing neuroleptic activity of thederivatives was determined using ³ H-spiroperidol binding to dopaminereceptor according to the method of Leysen et al., Biochem. Pharmacol.27, p. 307 (1978) and was adapted from that of Burt et al., Mol.Pharmacol. 12, pp. 800-812 (1976).

Rats (Sprague-Dawley CD males, 250-300 g, Charles River Laboratories,Wilmington, Mass.) were decapitated, and brains were immediatelydissected to recover the corpus striatum. The latter was homogenized in40 vol of ice-cold 50 mM Tris (tris[hydroxymethyl]-aminomethane).HClbuffer, pH 7.7 with a Brinkmann Polytron PT-10. The homogenate wascentrifuged twice at 50,000 g for 10 minutes at 0°-4° withrehomogenization of the intermediate pellet in fresh Tris buffer (samevolume) in the Polytron. The final pellet was gently resuspended in 90volumes of cold 50 mM Tris.HCl buffer, pH 7.6, containing 120 mM NaCl, 5mM KCl, 2 mM CaCl₂, 1 mM MgCl₂, 0.1% ascorbic acid, and 10 μM pargyline.The tissue suspension was placed in a 37° water bath for 5 minutes andkept ice cold until use. The incubation mixture consisted of 0.02 mlinhibitor solution or vehicle, 1.0 ml tissue preparation, and 0.10 ml ³H-spiroperidol (New England Nuclear, 23.6 Ci/mmol) prepared so as toobtain 0.5 nM final concentration. Tubes were incubated in sequence for10 minutes at 37° in groups of three, after which 0.9 ml from eachincubation tube was filtered through Whatman GF/B filters with vacuum.After washing twice with 5 ml of cold tris HCl buffer, pH 7.7, eachfilter was placed in a scintillation vial with 10 ml Aquasol-2 (NewEngland Nuclear), and each vial was vortexed. Samples were kept at roomtemperature overnight before determination of radioactivity in a liquidscintillation counter. Binding was calculated as fmoles of ³H-spiroperidol bound per milligram of protein. Controls (vehicle or 10⁻⁷M 1-butaclamol), blank (10⁻⁷ M d-butaclamol) and inhibitor solutions(four concentrations) were run in triplicate. The concentration thatreduced binding by 50% (IC₅₀) was estimated on semilog paper. The IC₅₀values in Table I represent means of two or three runs. Insoluble drugswere dissolved in ethanol (1-2% ethanol in final incubation mixture). Asillustrated in Table I, this intrinsic method shows that the compoundsof the present invention have excellent neuroleptic activity.

The present invention is illustrated by the following examples. However,it should be understood that the invention is not limited to thespecific details of these examples.

                                      TABLE I                                     __________________________________________________________________________    NEUROLEPTIC ACTIVITY OF 1HPYRIDO[4,3-b]INDOLES                                 ##STR35##                                                                                       Amphetamine      Inhibition                                Compound           Activity.sup.(b) H.sup.3Spiroperidol                       Structure.sup.(a)  (approx. ED.sub.50 mg/kg i.p.)                                                                 Binding.sup.(c)                           A/B                                                                              R.sup.1      n  1 hr.                                                                              5 hr. 24 hr.                                                                              IC.sub.50 (nM)                            __________________________________________________________________________    (A)                                                                               ##STR36##   4 4(+) 6                                                                         0.018 0.04 0.32-1                                                                  0.01-0.032 0.01 <0.32                                                               0.056 0.11  0.32-1                                                                  6.2 6.8 9.5                               (A)                                                                               ##STR37##   4 6                                                                              0.057 <0.1                                                                         0.008 <0.1                                                                          0.057 0.1-0.32                                                                       10 6.5                                   (A)                                                                               ##STR38##   4  >1   0.32-1.0                                                                            ˜0.32                                                                         28                                        (A)                                                                               ##STR39##   4  >1   0.32-1.0                                                                            ˜3.2                                                                          42                                        (A)                                                                               ##STR40##   4  0.18 0.11  0.36  12                                        (A)                                                                               ##STR41##   4  1-3.2                                                                              <3.2  3.2-10                                                                              29                                        (A)                                                                               ##STR42##   4  3.6  1.1   0.57  27                                        (A)                                                                               ##STR43##   2 3 6                                                                            0.57 0.11 0.18                                                                     0.57 0.05 0.033                                                                     >32 >0.32 >0.32                                                                     26 14 9.4                                 (A)                                                                               ##STR44##   4  -- ˜1.78.sup.(d)                                                             5.7 ˜1.78.sup.(d)                                                             -- 3.2-5.6.sup.(d)                                                                  29                                        (A)                                                                               ##STR45##   4  >10  1-3.2 >10   15                                        (A)                                                                               ##STR46##   2 4 2(+)                                                                         0.18 1-3.2 0.04                                                                    0.06 0.32-1.0 0.02                                                                  0.57  0.32-1.0 0.23                                                                 25 17 23                                  (A)                                                                               ##STR47##   4  3.2-10                                                                             ˜3.2                                                                          3.2-10                                                                              32                                        (B)                                                                              NHCOCH.sub.3 6  0.32-1.0                                                                           0.32-1.0                                                                            >10   8.8                                       (B)                                                                               ##STR48##   4  ˜1                                                                           ˜3.2                                                                          >10   4.0                                       (B)                                                                              NHCOOC.sub.2 H.sub.5                                                                       6  1-3.2                                                                              ˜3.2                                                                          >10   6.8                                          Chloropromazine 5.3  8.5   >32   51                                        __________________________________________________________________________     .sup.(a) Unless otherwise indicated by (+) or (-), the compound tested wa     the racemic (±) variant.                                                   .sup.(b) Entries are ranges within which fall the ED.sub.50 values for        blocking hyperactivity and stereotypy induced by amphetamine. Details are     given in the text.                                                            .sup.(c) IC.sub.50 values were estimated graphically usually using four       drug concentrations separated by 0.5 log unit. Entries are generally mean     of two or three determinations. For details, see the text.                    .sup.(d) Oral dosage.                                                    

EXAMPLE 1 1-(4-Chloro-1-butyl)-2-piperidone

Sodium hydride (3.87 g of 50% dispersion in oil, 0.0807 mole) wassuspended and stirred in 80 ml of dry dimethylformamide. A solution of1,4-dichlorobutane (44 ml, 0.404 mole) and 2-piperidone (8 g, 0.0807mole) in 100 ml of dimethylformamide was added dropwise over 1 hour,maintaining the temperature at 25°-30° C. by use of a water bath. Thereaction mixture was stirred for 16 hours at room temperature, thenbyproduct salt removed by filtration and the mother liquor evaporated invacuo to one-tenth volume. The resulting concentrate was distributedbetween 100 ml of water and 100 ml of hexane. The lower, oily phase ofthree phases was separated, diluted with 50 ml of methylene chloride,dried over magnesium sulfate, filtered and evaporated to yield1-(4-chloro-1-butyl)-2-piperidone as an oil [14.3 g; pnmr(CDCl₃)delta1.4-1.83 (4H, m), 3.03-3.72 (6H, m), 4.10-4.43 (2H, t, J=7)].

In like manner, 1,2-dichloroethane, 1,3-dichloropropane,1,5-dichloropentane, 1,4-dichloro-2-butene and 1,4-dichloro-2-butyne arereacted with 2-piperidone to yield respectively,1-(2-chloroethyl)-2-piperidone, 1-(3-chloro-1-propyl)-2-piperidone,1-(5-chloro-1-pentyl)-2-piperidone,1-(4-chloro-2-buten-1-yl)-2-piperidone,1-(4-chloro-2-butyn-1-yl)-2-piperidone.

In like manner, 6-chloro-1-hexanol is reacted with 2-piperidone toproduce 1-(6-hydroxy-1-hexyl)-2-piperidone. The latter is reacted withmethanesulfonyl chloride in methylene chloride in the presence of oneequivalent of triethylamine to yield1-(6-methanesulfonyloxy-1-hexyl)-2-piperidone.

In like manner, 1,4-dichlorobutane is reacted with 2-pyrrolidinone,6-hexanelactam (epsilon-caprolactam) and1,2,3,4-tetrahydro-2-benzo[b]pyridone to produce respectively,1-(4-chloro-1-butyl)-2-pyrrolidinone,N-(4-chloro-1-butyl)-6-hexanelactam and1-(4-chloro-1-butyl)-1,2,3,4-tetrahydro-2-benzo[b]pyridone.

In like manner, 2-hydroxypyrrole (tautomeric equivalent form of2-pyrrolin-5-one) and 2-hydroxyindole are reacted with1,4-dichlorobutane to produce respectively,1-(4-chloro-1-butyl)-2-hydroxypyrrole and1-(4-chloro-1-butyl)-2-hydroxyindole.

EXAMPLE 2(±)-8-Fluoro-5-(4-fluorophenyl)-2-[4-(2-piperidon-1-yl)-1-butyl]-2,3,4,4a,5,9b-hexahydro-4a,9b-trans-1-H-pyrido[4,3-b]indoleHydrochloride (Method A)

1-(4-Chloro-1-butyl)-2-piperidone (496 mg, 2.62 mmole),(±)-8-fluoro-5-(4-fluorophenyl)-2,3,4,4a,5,9b-hexahydro-4a,9b-trans-1H-pyrido[4,3-b]indole(500 mg, 1.75 mmole), anhydrous sodium carbonate (1.1 g, 10.4 mmole) andpotassium iodide (5 mg) were combined in 3-methyl-2-butanone (20 ml) andthe slurry refluxed for 16 hours. The reaction mixture was evaporated invacuo to solids, and the residue partitioned between 50 ml of methylenechloride and 50 ml of water. The aqueous phase was washed with 50 ml offresh methylene chloride. The organic layers were combined, dried overanhydrous magnesium sulfate, filtered and evaporated to a gum. The gumwas chromatographed on silica gel with 1:10 methanol:ethyl acetate aseluant and tlc monitoring. Clean product-containing fractions werecombined and evaporated to a second gum. The second gum was taken intomethylene chloride, converted to hydrochloride salt by the addition ofethereal hydrogen chloride, and the mixture reevaporated to a foam. Thefoam was slurried with 50 ml of ether and filtered to yield the titleproduct [532 mg, Rf 0.4 (1:4 methanol:ethyl acetate); ir(KBr) 1215,1468, 1503, 1605, 2924, 3394 cm⁻¹ ].

In like manner, 1-(2-chloroethyl)-2-piperidone,1-(3-chloro-1-propyl)-2-piperidone, 1-(5-chloro-1-pentyl)-2-piperidone,1-(6-methanesulfonyloxy-1-hexyl)-2-piperidone,1-(4-chloro-1-butyl)-2-pyrrolidinone,N-(4-chloro-1-butyl)-6-hexanelactam,1-(4-chloro-1-butyl)-1,2,3,4-tetrahydro-2-benzo[b]pyridine,1-(4-chloro-2-buten-1-yl)-2-piperidone and1-(4-chloro-2-butyn-1-yl)-2-piperidone of the preceding Example areconverted, respectively, to:

(±)-8-fluoro-5-(4-fluorophenyl)-2-[2-(2-piperidon-1-yl)ethyl]-2,3,4,4a,5,9b-hexahydro-4a,9b-trans-1H-pyrido[4,3-b]indolehydrochloride;

(±)-8-fluoro-5-(4-fluorophenyl)-2-[3-(2-piperidon-1-yl)-1-propyl]-2,3,4,4a,5,9b-hexahydro-4a,9b-trans-1H-pyrido[4,3-b]indolehydrochloride;

(±)-8-fluoro-5-(4-fluorophenyl)-2-[5-(2-piperidon-1-yl)-1-pentyl]-2,3,4,4a,5,9b-hexahydro-4a,9b-trans-1H-pyrido[4,3-b]indolehydrochloride;

(±)-8-fluoro-5-(4-fluorophenyl)-2-[5-(2-piperidon-1-yl)-1-hexyl)-2,3,4,4a,5,9b-hexahydro-4a,9b-trans-1H-pyrido[4,3-b]indolehydrochloride;

(±)-8-fluoro-5-(4-fluorophenyl)-2-[4-(2-pyrrolidinon-1-yl)-1-butyl]-2,3,4,4a,5,9b-hexahydro-4a,9b-trans-1H-pyrido[4,3-b]indolehydrochloride;

(±)-8-fluoro-5-(4-fluorophenyl)-2-[4-(2-perhydroazepinon-1-yl)-1-butyl]-2,3,4,4a,5,9b-hexahydro-4a,9b-trans-1H-pyrido[4,3-b]indolehydrochloride;

(±)-8-fluoro-5-(4-fluorophenyl)-2-[4-(1,2,3,4,-tetrahydro-2-benzo[b]pyridon-1-yl)-1-butyl]-2,3,4,4,a,5,9b-hexahydro-4a,9b-trans-pyrido[4,3-b]indole

(±)-8-fluoro-5-(4-fluorophenyl)-2-[4-(2-piperidon-1-yl)-2-buten-1-yl]-2,3,4,4a,5,9b-hexahydro-4a,9b-trans-1H-pyrido[4,3-b]indolehydrochloride; and

(±)-8-fluoro-5-(4-fluorophenyl)-2-[4-(2-piperidon-1-yl)-2-butyn-1-yl]-2,3,4,4a,5,9b-hexahydro-4a,9b-trans-1H-pyrido[4,3-b]indolehydrochloride.

In like manner, 1-(4-chloro-1-butyl-2-hydroxypyrrole and1-(4-chloro-1-butyl)-2-hydroxyindole of Example 1 are converted,respectively, to:

(±)-8-fluoro-5-(4-fluorophenyl)-2-[4-(2-hydroxy-1-pyrrolyl)-1-butyl]-2,3,4,4a,5,9b-hexahydro-4a,9b-trans-1H-pyrido[4,3-b]indole;and

(±)-8-fluoro-5-(4-fluorophenyl)-2-[4-(2-hydroxy-1-indolyl)-1-butyl]-2,3,4,4a,5,9b-hexahydro-4a,9b-trans-1H-pyrido[4,3-b]indole.

The last two named compounds are tautomeric forms, respectively, of:

(±)-8-fluoro-5-(4-fluorophenyl)-2-[4-(2-pyrrolin-5-on-1-yl)-1-butyl]-2,3,4,4a,5,9b-hexahydro-4a,9b-trans-1H-pyrido[4,3-b]indole;and

(±)-8-fluoro-5-(4-fluorophenyl)-2-[4-(2,3-dihydro-2-indolon-1-yl)-1-butyl]-2,3,4,4a,5,9b-hexahydro-4a,9b-trans-1H-pyrido[4,3-b]indole.

In like manner, 1-(4-chloro-1-butyl)-2-piperidone is reacted with theappropriately substituted5-phenyl-2,3,4,4a,5,9b-hexahydro-4a,9b-trans-1H-pyrido[4,3-b]indole toprepare:

(±)-5-phenyl-2-[4-(2-piperidon-1-yl)-1-butyl]-2,3,4,4a,5,9b-hexahydro-4a,9b-trans-1H-pyrido[4,3-b]indole;

(±)-8-fluoro-5-(4-fluorophenyl)-2-[4-(2-piperidon-1-yl)-1-butyl]-2,3,4,4a,5,9b-hexahydro-4a,9b-trans-1H-pyrido[4,3-b]indole;

(±)-8-fluoro-5-(3-fluorophenyl)-2-[4-(2-piperidon-1-yl)-1-butyl]-2,3,4,4a,5,9b-hexahydro-4a,9b-trans-1H-pyrido[4,3-b]indole;

(±)-5-(2-fluorophenyl)-2-[4-(2-piperidon-1-yl)-1-butyl]-2,3,4,4a,5,9b-hexahydro-4a,9b-trans-1H-pyrido[4,3-b]indole;

(±)-8-chloro-5-(4-chlorophenyl)-2-[4-(2-piperidon-1-yl)-1-butyl]-2,3,4,4a,5,9b-hexahydro-4a,9b-trans-1H-pyrido[4,3-b]indole;and

(±)-5-(3-methoxyphenyl)-2-[4-(2-piperidon-1-yl)-1-butyl]-2,3,4,4a,5,9b-hexahydro-4a,9b-trans-1H-pyrido[4,3-b]indole.

(±)-8-chloro-5-(4-fluorophenyl)-2-[4-(2-piperidon-1-yl)-1-butyl]-2,3,4,4a,5,9b-hexahydro-4a,9b-trans-1H-pyrido[4,3-b]indole;

(±)-8-bromo-5-(4-bromophenyl)-2-[4-(2-piperidon-1-yl)-1-butyl]-2,3,4,4a,5,9b-hexahydro-4a,9b-trans-1H-pyrido[4,3-b]indole;

(±)-8-methyl-5-phenyl-2-[4-(2-piperidon-1-yl)-1-butyl]-2,3,4,4a,5,9b-hexahydro-4a,9b-trans-1H-pyrido[4,3-b]indole;

(±)-8-fluoro-5-(2-methoxyphenyl)-2-[4-(2-piperidon-1-yl)-1-butyl]-2,3,4,4a,5,9b-hexahydro-4a,9b-trans-1H-pyrido[4,3-b]indole;

(±)-8-fluoro-5-(3-methylphenyl)-2-[4-(2-piperidon-1-yl)-1-butyl]-2,3,4,4a,5,9b-hexahydro-4a,9b-trans-1H-pyrido[4,3-b]indole;and

(±)-8-fluoro-5-(4-methyl-2-methoxyphenyl)-2-[4-(2-piperidon-1-yl)-1-butyl]-2,3,4,4a,5,9b-hexahydro-4a,9b-trans-1H-pyrido[4,3-b]indole.

EXAMPLE 3(±)-8-Fluoro-5-(4-fluorophenyl)-2-[4-(2-piperidon-1-yl)-2-butyn-1-yl]-2,3,4,4a,5,9b-hexahydro-4a,9b-trans-1H-pyrido[4,3-b]indole

Sodium hydride (5.76 g of 50% dispersion in oil, 0.12 mole) was washedthree times with hexane and suspended in 645 ml of toluene. 2-Piperidone(11.88 g, 0.12 mole) in 100 ml of toluene was added to the well stirredsodium hydride suspension and heated to reflux for 2 hours. The reactionmixture was cooled to 15° C. and 2-propynyl bromide (14.28 g, 0.12 mole)in 55 ml of toluene added over 30 minutes. The mixture was then stirredat room temperature for 19 hours, filtered and mother liquor evaporatedto yield a first batch of 1-(2-propynyl)-2-piperidone as an oil (7.87 gof about 55% purity by pnmr assay).

In a second run the level of sodium hydride dispersion was increased to7.2 g, suspended in 500 ml of tetrahydrofuran rather than toluene. Forisolation, the reaction mixture was poured cautiously onto a mixture ofconcentrated hydrochloric acid (17 ml, 0.20 mole) and 300 ml of ice. Thequenched reaction mixture was extracted with three portions of ethylacetate. The organic extracts were combined, dried over anhydrousmagnesium sulfate, filtered and evaporated to yield a second batch of1-(2-propynyl)-2-piperidone (13 g of about 50% purity by pnmr assay).

(±)-8-Fluoro-5-(3-fluorophenyl)-2,3,4,4a,5,9b-hexahydro-4a,9b-trans-1H-pyrido[4,3-b]indolehydrochloride (11.0 g, 34.2 mmoles) was converted to free base bydistribution between ethyl acetate and excess dilute sodium hydroxide.The ethyl acetate layer was separated, dried over anhydrous magnesiumsulfate, filtered and evaporated to dryness in vacuo. The resulting gumwas dissolved in 450 ml of absolute ethanol. Formaldehyde (3.41 ml of30% in water, 34.2 mmoles) was added and the stirred solution warmed to35° C. Cuprous chloride (5.1 g) and then a mixture of first and secondbatches of 1-(2-propynyl)-2-piperidone (4.67 g by assay, 34.2 mmoles)were added. The resulting suspension was stirred for 18 hours at roomtemperature. The reaction mixture was clarified by filtration withethanol wash and the combined filtrate/wash evaporated to a gum. The gumwas dissolved in the minimum volume of 9:1 ethyl acetate:methanol andchromatographed on 650 g of silica gel with first ethyl acetate and then9:1 ethyl acetate:methanol as eluant, and monitoring by tlc. Cleanmiddle cuts were combined and evaporated to dryness to yield the titleproduct [12.5 g; Rf 0.75 (1:10 ethyl acetate:methanol)] in the form ofits free base. A portion of this free base (0.5 g) was dissolved in 50ml of ether. The stirred solution was saturated with hydrogen chlorideand left to stand for two days. The title product was recovered ascrystalline solid by filtration [247 mg, m.p. 123°-125° C., [alpha]_(D)²⁵ =+13.78° (methanol, c=0.73)].

Analysis: Calcd. for C₂₆ H₂₇ ON₃ F₂.HCl.1.5H₂ O: C, 62.57; H, 6.26; N,8.42. Found: C, 62.37; H, 6.25; N, 8.20.

EXAMPLE 4(±)-8-Fluoro-5-(4-fluorophenyl)-2-[4-(2-piperidon-1-yl)-1-butyl]-2,3,4,4a,5,9b-hexahydro-4a,9b-trans-1H-pyrido[4,3-b]indole(Method B)

Free base form of the compound of the preceding Example (12.4 g) wasdissolved in 270 ml of absolute ethanol. Catalyst (5% Pd/C, 3 g) wasadded and the mixture hydrogenated at room temperature for 90 minutes,in which time uptake of hydrogen was complete. Catalyst was recovered byfiltration and the filtrate evaporated to a gum. The gum waschromatographed on 250 g of silica gel with 9:1 ethyl acetate:methanolas eluant and monitoring by tlc. Clean product-containing fractions wereevaporated to yield the title product [8.6 g, Rf 0.3 (9:1 ethylacetate:methanol); [alpha]_(D) ²³ =+15.8° (methanol, c=0.5)] as the freebase. Free base (87 mg) and benzenesulfonic acid (35 mg) gave thebenzene sulfonate salt of the title product (84 mg, m.p. 138°-141° C.).Free base (85 mg) and benzoic acid (26 mg) similarly gave the benzoatesalt (m.p. 42°-44° C.) and maleic acid similarly gave a maleate salt(m.p. ca 80° C.).

In like manner,(±)-8-fluoro-5-(4-fluorophenyl)-2-[4-(2-piperidon-1-yl)-2-buten-1-yl]-2,3,4,4a,5,9b-hexahydro-4a,9b-trans-1H-pyrido[4,3-b]indolehydrochloride is hydrogenated to(±)-8-fluoro-5-(4-fluorophenyl)-2-[4-(2-piperidon-1-yl)-1-butyl]-2,3,4,4a,5,9b-hexahydro-4a,9b-trans-1H-pyrido[4,3-b]indole.

EXAMPLE 5(±)-8-Fluoro-5-(4-fluorophenyl)-2-[4-(2-piperidon-1-yl)-1-butyl]-2,3,4,4a,5,9b-hexahydro-4a,9b-trans-1H-pyrido[4,3-b]indoleBis(dihydrogenphosphate)

Free base form of the title compound (7.2 g, 16.4 mmoles) was dissolvedin 200 ml of ethyl acetate. With strong stirring, phosphoric acid (3.76g of 85.5%, 32.8 mmoles) in 20 ml of ethyl acetate was added dropwise,precipitating the desired salt in crude form (12 g). The crude wasdissolved in 50 ml of boiling methanol. Ethyl acetate (50 ml) was addedand the mixture cooled slowly to room temperature. Purified titleproduct was recovered by filtration and dried in vacuo over phosphoruspentoxide (8.49 g, m.p. 197°-8° C.; [alpha]_(D) ²³ =+16.61°).

Analysis: Calcd. for C₂₆ H₃₁ ON₃ F₂.(H₃ PO₄)₂ : C, 49.14; H, 5.87; N,6.62. Found: C, 48.93; H, 5.84; N, 6.68.

EXAMPLE 6 1-(6-Bromo-1-hexyl)-2-piperidone

Following the procedure of Example 1, sodium hydride (3.63 g of 50%dispersion in oil, 0.15 mole), 1,6-dibromohexane (23.07 ml, 0.15 mole)and 2-piperidone (7.5 g, 0.076 mole) were reacted in dimethylformamide.The filtered, concentrated reaction mixture was taken up in 200 ml ofwater and 200 ml of hexane. The hexane layer was separated andevaporated to an oil. The oil was chromatographed on silica gel usingethyl acetate as eluant and tlc monitoring. Clean product-containingfractions were combined and evaporated to yield1-(6-bromo-1-hexyl)-2-piperidone as an oil (3.66 g).

In like manner 3-bromo-1-chloropropane, 1,3-dibromopropane,1-bromo-4-chlorobutane, 1,4-dibromobutane, 1,4-dibromo-2-butene,1,5-dibromopentane, 1,7-dibromoheptane, 1,8-dibromooctane and1,9-dibromononane are reacted with 2-piperidone to yield, respectively,1-(3-bromo-1-propyl)-2-piperidone, 1-(4-chloro-1-butyl)-2-piperidone,1-(4-bromo-1-butyl)-2-piperidone, 1-(5-bromo-1-pentyl)-2-piperidone,1-(7-bromo-1-heptyl)-2-piperidone, 1-(8-bromo-1-octyl)-2-piperidone and1-(9-bromo-1-nonyl)-2-piperidone.

EXAMPLE 7(±)-8-Fluoro-5-(4-fluorophenyl)-2-[6-(2-piperidon-1-yl)-1-hexyl]-2,3,4,4a,5,9b-hexahydro-4a,9b-trans-1H-pyrido[4,3-b]indoleHydrochloride (Method A)

Free base of the title product was prepared in crude form from1-(6-bromo-1-hexyl)-2-piperidone by the procedure of Example 1, but ontwice the scale. Purification was achieved by chromatography on silicagel with 1:9 methanol:ethyl acetate as eluant. Product fractions werecombined, diluted with excess ethereal hydrogen chloride and evaporatedto yield the title product as a solid (1.4 g).

Analysis: Calcd. for C₂₈ H₃₅ ON₃ F₂.HCl.0.75H₂ O: C, 64.97; H, 7.34; N,8.11. Found: C, 64.84; H, 7.04; N, 7.96.

In like manner, 1-(3-bromo-1-propyl)-2-piperidone,1-(4-chloro-1-butyl)-2-piperidone and 1-(4-bromo-1-butyl)-2-piperidone,1-(5-bromo-1-pentyl)-2-piperidone, 1-(7-bromo-1-heptyl)-2-piperidone,1-(7-bromo-1-octyl)-2-piperidone, and 1-(7-bromo-1-nonyl)-2-piperidoneare converted, respectively, to:

(±)-8-fluoro-5-(4-fluorophenyl)-2-[3-(2-piperidon-1-yl)-1-propyl]-2,3,4,4a,5,9b-hexahydro-4a,9b-trans-1H-pyrido[4,3-b]indolehydrochloride;

(±)-8-fluoro-5-(4-fluorophenyl)-2-[4-(2-piperidon-1-yl)-1-butyl]-2,3,4,4a,5,9b-hexahydro-4a,9b-trans-1H-pyrido[4,3-b]indolehydrochloride;

(±)-8-fluoro-5-(4-fluorophenyl)-2-[5-(2-piperidon-1-yl)-1-pentyl]-2,3,4,4a,5,9b-hexahydro-4a,9b-trans-1H-pyrido[4,3-b]indolehydrochloride;

(±)-8-fluoro-5-(4-fluorophenyl)-2-[7-(2-piperidon-1-yl)-1-heptyl]-2,3,4,4a,5,9b-hexahydro-4a,9b-trans-1H-pyrido[4,3-b]indolehydrochloride;

(±)-8-fluoro-5-(4-fluorophenyl)-2-[8-(2-piperidon-1-yl)-1-octyl]-2,3,4,4a,5,9b-hexahydro-4a,9b-trans-1H-pyrido[4,3-b]indolehydrochloride; and

(±)-8-fluoro-5-(4-fluorophenyl)-2-[9-(2-piperidon-1-yl)-1-nonyl]-2,3,4,4a,5,9b-hexahydro-4a,9b-trans-1H-pyrido[4,3-b]indolehydrochloride.

EXAMPLE 8(±)-8-Fluoro-5-(4-fluorophenyl)-2-(4-chloro-1-butyl)-2,3,4,4a,5,9b-hexahydro-4a,9b-trans-1H-pyrido[4,3-b]indoleHydrochloride

4-Chlorobutyryl chloride (1.0 g, 7.1 mmoles),(±)-8-fluoro-5-(4-fluorophenyl)-2,3,4,4a,5,9b-hexahydro-4a,9b-trans-1H-pyrido[4,3-b]indole(2 g, 7 mmoles), and anhydrous sodium carbonate (1.5 g) are combined in80 ml of 2-butanone and stirred at room temperature for 2 hours. Thereaction mixture is evaporated to dryness and the residue distributedbetween 200 ml of methylene chloride and 200 ml of water. The waterphase is washed with additional methylene chloride. The combined organiclayers are evaporated to yield(±)-8-fluoro-5-(4-fluorophenyl)-2-(4-chlorobutyryl)-2,3,4,4a,5,9b-hexahydro-4a,9b-trans-1H-pyrido[4,3-b]indole.The latter is added to a stirred suspension of lithium aluminum hydride(0.19 g, 5 mmoles) in 35 ml of diethyl ether, keeping the temperature25°-30° C. by the rate of addition. After stirring for 4 hours at roomtemperature, Glauber's salt (Na₂ SO.sub. 4.10H₂ O; 1.5 g, 5 mmoles) isadded portionwise over a 10 minute period. The mixture is filtered, andthe filtrate acidified with ethereal hydrogen chloride and evaporated toyield the title product (hydrochloride salt). Free base, when desired,is regenerated immediately before use.

The corresponding 4-bromo-1-butyl derivative is prepared in like mannerby substituting an equivalent amount of 4-bromobutyryl chloride in thefirst step of this two-step process.

EXAMPLE 9(±)-8-Fluoro-5-(4-fluorophenyl)-2-[4-(2-piperidon-1-yl)-1-butyl)-2,3,4,4a5,9b-hexahydro-4a,9b-trans-1H-pyrido[4,3-b]indoleHydrochloride (Method C)

At room temperature, sodium hydride (0.39 g of 50% dispersion in oil,8.1 mmoles) is suspended and stirred in 8 ml of dimethylformamide.2-Piperidone (0.8 g, 8.1 mmoles) in 5 ml of dimethylformamide is addeddropwise over 1 hour. Then(±)-8-fluoro-5-(4-fluorophenyl)-2-(4-chloro-1-butyl)-2,3,4,4a,5,9b-hexahydro-4a,9b-trans-1H-pyrido[4,3-b]indole(2.97 g, 7.9 mmoles) in 5 ml of dimethylformamide is added over 5minutes and the resulting mixture stirred for 48 hours at roomtemperature. Salts are removed by filtration and the mother liquorevaporated to dryness in vacuo. The crude product is further purifiedaccording to the methods detailed in Example 2.

In like manner, the corresponding 4-bromobutyl derivative of thepreceding Example is also converted to the title product.

EXAMPLE 108-Fluoro-5-(4-fluorophenyl)-2-(3-cyano-1-propyl)-2,3,4,4a,5,9b-hexahydro-4a,9b-trans-1H-pyrido[4,3-b]indole

A stirred suspension of8-fluoro-5-(4-fluorophenyl)-2,3,4,4a,5,9b-hexahydro-4a,9b-trans-1H-pyrido[4,3-b]-indole(1 g, 3.49 mmoles), 4-bromobutanenitrile (0.723 g, 4.88 mmoles),anhydrous sodium carbonate (2.1 g, 20.9 mmoles), potassium iodide (0.289g, 1.74 mmoles) in methylisobutylketone (40 ml) was refluxed undernitrogen for 16 hours. The reaction mixture was cooled to roomtemperature and evaporated in vacuo to dryness. The resulting whitesolid was partitioned between water (40 ml) and chloroform (50 ml). Thephases were separated and the aqueous phase extracted with chloroform(50 ml). The organic layers were combined, dried (MgSO₄), and evaporatedin vacuo to give a pale yellow oil. Treatment of the oil with hydrogenchloride gas in acetone (40 ml) gave upon filtration and washing withacetone (10 ml) 0.813 g, (60% yield) of the above titled nitrileintermediate as a white solid, m.p. 245°-249° C. (HCl salt).

Analysis: Calcd. for C₂₁ H₂₁ N₃ F₂.HCl: C, 64.67; H, 5.42; N, 10.77.Found: C, 64.38; H, 5.71; N, 10.71.

EXAMPLE 11(±)-8-Fluoro-5-(4-fluorophenyl)-2-(4-amino-1-butyl)-2,3,4,4a,5,9b-hexahydro-4a,9b-trans-1H-pyrido[4,3-b]indoleHydrochloride

To a stirred suspension of lithium aluminum hydride (0.167 g, 4.4mmoles) in diethyl ether (35 ml), under nitrogen, was added the nitrileintermediate of the preceding Example (0.781 g, 2.0 mmoles) at a ratesufficient to maintain the reaction temperature 28°-30° C. (15 minutes).After stirring for 4 hours at ambient temperature, Glauber's salt (Na₂SO₄.10H₂ O; 1.2 g, 4 mmoles) was added portionwise over a 10 minuteperiod. The white solid was filtered and washed with diethyl ether (10ml) and the filtrate evaporated in vacuo to give a pale yellow oil.Treatment of the oil with hydrogen chloride in ether (35 ml) gave uponfiltration and washing with ether (20 ml), 0.498 g, (64% yield) of theabove titled compound as a white solid m.p. 224°-227° C. (HCl salt).

Analysis: Calcd. for C₂₁ H₂₅ N₃ F₂.2.5H₂ O.HCl: C, 53.28; H, 6.38; N,8.87. Found: C, 52.98; H, 5.94; N, 8.66.

EXAMPLE 12(±)-8-Fluoro-5-(4-fluorophenyl)-2-[4-(5-chlorovaleramido)-1-butyl]-2,3,4,4a,5,9b-hexahydro-1H-pyrido[4,3-b]indole

The amine of the preceding Example (3.15 g, 8.03 mmoles) andtriethylamine (4.4 ml, 32 mmoles) are dissolved in methylene chloride(100 ml), under nitrogen at 2° C. (ice bath). 5-Chlorovaleryl chloride(13.6 g, 8.8 mmoles) in 5 ml methylene chloride is added at a ratesufficient to maintain the reaction temperature 2°-5° C. After stirringat ambient temperature for 2 hours, the reaction mixture is poured ontosaturated sodium bicarbonate solution (30 ml). The phases are separatedand the aqueous phase extracted with methylene chloride (30 ml). Theorganic layers are combined, dried (MgSO₄), and evaporated to dryness invacuo to yield the title product.

EXAMPLE 13(±)-8-Fluoro-5-(4-fluorophenyl)-2-[4-(2-piperidon-1-yl)-1-butyl]-2,3,4,4a,5,9b-hexahydro-4a,9b-trans-1H-pyrido[4,3-b]indoleHydrochloride (Method D)

Sodium hydride (0.38 g of 50% dispersion in oil, 7.9 mmoles) issuspended and stirred in 8 ml of dimethylformamide and added dropwise toa solution of the chlorovaleramide of the preceding Example (3.75 g, 7.9mmoles) in 12 ml of dimethylformamide. The mixture is stirred at ambienttemperature for 48 hours, filtered and the mother liquor evaporated todryness to yield crude title product. The crude is purified by themethods detailed in Example 2.

EXAMPLE 14 Ethyl(±)-5-[[4-[8-Fluoro-5-(4-fluorophenyl)-2,3,4,4a,5,9-hexahydro-4a,9b-trans-1H-pyrido[4,3-b]indol-2-yl]-1-butylamino]valerate

8-Fluoro-5-(4-fluorophenyl)-2-(4-bromo-1-butyl)-2,3,4,4a,5,9-hexahydro-4a,9b-trans-1H-pyrido[4,3-b]indole(4.2 g, 10 mmoles) is dissolved in 35 ml of dimethyl formamide and addeddropwise over 8 hours to a solution of ethyl 5-aminovalerate (6.5 g, 50mmoles) in 35 ml of the same solvent maintained at 35° C. Aftermaintaining for an additional 4 hours at this temperature, the reactionmixture is evaporated to dryness in vacuo. The residue is chased withadditional dimethylformamide and pumped under high vacuum in a rotatingevaporator to remove excess ethyl 5-aminovalerate to yield the titleproduct.

EXAMPLE 15(±)-8-Fluoro-5-(4-fluorophenyl)-2-[4-(2-piperidon-1-yl)-1-butyl]-2,3,4,4a,5,9b-hexahydro-4a,9b-trans-1H-pyrido[4,3-b]indoleHydrochloride (Method E)

The ethyl ester of the preceding Example (4.7 g, 10 mmoles) is taken upin 200 ml of methyl isobutyl ketone. Anhydrous sodium carbonate (10.6 g,0.1 mole) is added, and the mixture refluxed for 16 hours. The titleproduct is isolated and purified according to the methods of Example 2.

EXAMPLE 16 3-(4-Chloro-1-butyl)-2-oxazolidinone

Following the procedure of Piper et al. [J. Het. Chem. 4, p. 298(1967)], sodium hydride (4.8 g of 50% dispersion in oil, 0.1 mole) waswashed with pentane and suspended in 20 ml of dimethylformamide. Asolution of 2-oxazolidinone (8.7 g, 0.10 mole) and 1,4-dichlorobutane(66 g, 0.52 mole) in 100 ml of dimethylformamide was then added dropwiseover 30 minutes, maintaining the reaction temperature at 25°-30° C. Thereaction was stirred for 18 hours at ambient temperature, thenevaporated to an oil, and the oil taken up in ethyl acetate, treatedwith activated carbon, filtered over diatomaceous earth, andreevaporated in vacuo to yield the title product as an oil [16.5 g,contaminated with mineral oil from incompletely washed sodium hydride;pnmr/CDCl₃ /delta; 0.67-1.0 and 1.03-1.4 (mineral oil), 1.4-1.83 (m,4H), 3.03-3.72 (m, 6H), 4.10-4.43 (t, 2H)].

In like manner, 1,3-dichloropropane and 1-chloro-3-bromopropane are eachconverted to 3-(3-chloro-1-propyl)-2-oxazolidinone, and1,5-dichloropentane is converted to3-(5-chloro-1-pentyl)-2-oxazolidinone.

In like manner, 4-oxazolidinone, 2-thiazolidinone, 2-oxazolone,2-thiazolone and 3-morpholone are converted, respectively, to3-(4-chloro-1-butyl)-4-oxazolidinone,3-(4-chloro-1-butyl)-2-thiazolidinone, 3-(4-chloro-1-butyl)-2-oxazolone,3-(4-chloro-1-butyl)-2-thiazolone and 4-(4-chloro-1-butyl)-3-morpholone.

EXAMPLE 17(±)-8-Fluoro-5-(4-fluorophenyl)-2-[4-(2-oxazolidinon-3-yl)-1-butyl]-2,3,4,4a,5,9b-hexahydro-4a,9b-trans-1H-pyrido[4,3-b]indoleHydrochloride

By the procedure of Example 2, 1-(4-chloro-1-butyl)-2-oxazolidinone(0.93 g, 5.2 mmole) and(±)-8-fluoro-5-(4-fluorophenyl)-2,3,4,4a,5,9b-hexahydro-4a,9b-trans-1H-pyrido[4,3-b]indole(1.0 g, 3.5 mmoles) were reacted in 40 ml of 3-methyl-2-butanone in thepresence of sodium carbonate (1.46 g, 13.8 mmoles) to yield, withoutchromatography, the free base of the title product in the form of a gum.The gum was taken up in a mixture of 10 ml of 2-propanol and 10 ml ofacetone and converted to the hydrochloride salt by the addition ofexcess ethereal hydrogen chloride. The title product slowly crystallizedand was recovered by filtration [1.02 g; Rf 0.65 (7:1 ethylacetate:methanol); ir (KBr) 1181, 1219, 1258, 1477, 1513, 1760 cm⁻¹ ].

In like manner, 3-(3-chloro-1-propyl)-2-oxazolidinone,3-(5-chloro-1-pentyl)-2-oxazolidinone,3-(4-chloro-1-butyl)-4-oxazolidinone, 3-(4-chloro-1-butyl)-2-oxazolone,3-(4-chloro-1-butyl)-2-thiazolone, and 4-(4-chloro-1-butyl)-3-morpholoneare converted, respectively, to:

(±)-8-fluoro-5-(4-fluorophenyl)-2-[3-(2-oxazolidinon-3-yl)-1-propyl]-2,3,4,4a,5,9b-hexahydro-4a,9b-trans-1H-pyrido[4,3-b]indolehydrochloride;

(±)-8-fluoro-5-(4-fluorophenyl)-2-[5-(2-oxazolidinon-3-yl)-1-pentyl]-2,3,4,4a,5,9b-hexahydro-4a,9b-trans-1H-pyrido[4,3-b]indolehydrochloride;

(±)-8-fluoro-5-(4-fluorphenyl)-2-[4-(4-oxazolidinon-3-yl)-1-butyl]-2,3,4,4a,5,9b-hexahydro-4a,9b-trans-1H-pyrido[4,3-b]indolehydrochloride;

(±)-8-fluoro-5-(4-fluorophenyl)-2-[4-(2-oxazolidinon-3-yl)-1-butyl]-2,3,4,4a,5,9b-hexahydro-4a,9b-trans-1H-pyrido[4,3-b]indolehydrochloride;

(±)-8-fluoro-5-(4-fluorophenyl)-2-[4-(2-thiazolon-3-yl)-1-butyl]-2,3,4,4a,5,9b-hexahydro-4a,9b-trans-1H-pyrido[4,3-b]indolehydrochloride; and

(±)-8-fluoro-5-(4-fluorophenyl)-2-[4-(3-morpholon-4-yl)-1-butyl]-2,3,4,4a,5,9b-hexahydro-4a,9b-trans-1H-pyrido-[4,3-b]indole.

EXAMPLE 18 3-(6-Bromohexyl)-2-oxazolidinone

By the procedure of Example 1, sodium hydride (3.85 g of 50% dispersionin oil, 0.0804 mole), 1,6-dibromohexane (24.5 ml, 0.16 mole) and2-oxazolidinone (7.0 g, 0.0804 mole) in dimethylformamide (180 ml total)were reacted and the reaction mixture concentrated to one tenth volume.Hexane (200 ml) was added, salts were removed by filtration, and theheavy, oily layer separated from the filtrate. This heavy layer waschromatographed on silica gel with ethyl acetate as eluant and tlcmonitoring. Clean product-containing fractions were combined andevaporated to yield the title product as an oil [1.59 g; Rf 0.5 (ethylacetate)].

EXAMPLE 19(±)-8-Fluoro-5-(4-fluorophenyl)-2-[4-(2-oxazolidinon-3-yl)-1-hexyl-2,3,4,4a,5,9b-hexahydro-4a,9b-trans-1H-pyrido[4,3-b]indoleHydrochloride

By the procedure of Example 2, 3-(6-bromo-1-hexyl)-2-oxazolidinone (1.59g, 63.5 mmole) and the pyridoindole (0.91 g, 31.8 mmoles) wereconverted, without chromatography, to the free base form of the titleproduct, isolated as a gum. The gum was taken up in 30 ml of acetone,excess ethereal hydrogen chloride was added, and the mixture evaporatedto dry solids. The solids were repulped in a mixture of 30 ml of ethylacetate and 5 ml of acetone to yield the title product in purified form(0.90 g).

Analysis: Calcd. for C₂₆ H₃₁ O₂ N₃ F₂.HCl.0.75 H₂ O: C, 61.77; H, 6.72;N, 8.31. Found: C, 61.72; H, 6.44; N. 8.02.

EXAMPLE 20 3-(4-Chloro-1-butyl)-2,3-dihydro-2-benz[d]oxazolone

By the procedure of Example 1, 2,3-dihydro-2-benz[d]oxazolone("2-benzoxazolinone", Aldrich Chemical Co., 5 g, 0.037 mole) wasconverted to the title product. The product was isolated by filtrationof the reaction mixture to remove salts and evaporation in vacuo to anoil. The oil was extracted with hexane and further dried by vacuumevaporation (0.8 g).

EXAMPLE 21(±)-8-Fluoro-5-(4-fluorophenyl)-2-[4-(2,3-dihydro-2-benz[d]-oxazolon-3-yl)-1-butyl]-2,3,4,4a,5,9b-hexahydro-4a,9b-trans-1H-pyrido[4,3-b]indoleHydrochloride

By the procedure of Example 2, the chlorobutyl compound of the precedingExample (0.79 g, 3.5 mmoles) was reacted with(±)-8-fluoro-5-(4-fluorophenyl)-2,3,4,4a,5,9b-hexahydro-4a,9b-trans-1H-pyridoindole(500 mg, 1.75 mmole). The reaction mixture was filtered and the filtrateevaporated to a first gum. This first gum was chromatographed on silicagel with ethyl acetate as eluant and tlc monitoring. Clean productfractions were combined and the free base form of the title productisolated as a second gum by evaporation in vacuo. The second gum wasdissolved in ether and excess ethereal hydrogen chloride was added. Theresulting slurry was evaporated to obtain the title product as a solid[0.72 g, Rf 0.6 (ethyl acetate)].

Analysis: Calcd. for C₂₃ H₂₇ O₂ N₃ F₂.HCl.0.5 H₂ O: C, 64.55; H, 5.56;N, 8.06. Found: C, 64.20; H, 5.02; N, 8.03.

EXAMPLE 22(±)-8-Fluoro-5-(4-fluorophenyl)-2-[4-(4-imidazolin-2-on-1-yl)-1-butyl]-2,3,4,4a,5,9b-hexahydro-4a,9b-trans-1H-pyrido[4,3-b]indole

(±)-8-Fluoro-5-(4-fluorophenyl)-2-(4-bromo-1-butyl)-2,3,4,4a,5,9b-hexahydro-4a,9b-trans-1H-pyrido[4,3-b]indoleof Example 8 is reacted with 4-imidazolin-2-on (5-equivalents) by theprocedure of Example 9, using 1 equivalent of sodium hydride. Theproduct is isolated by partial evaporation in vacuo, removal of salts byfiltration and evaporation of the filtrate to dryness in vacuo. Removalof excess 4-imidazolin-2-one is facilitated by several chases withdimethylformamide.

It is understood that the tautomeric equivalent of the title product is(±)-8-fluoro-5-(4-fluorophenyl)-2-[4-(2-hydroxy-1-imidazolyl)-1-butyl]-2,3,4,4a,5,9b-hexahydro-4a,9b-trans-pyrido[4,3-b]indole.

Substitution of the 5 equivalents of 4-imidazolin-2-one in this processwith 1 to 1.1 equivalents of 1-methyl-4-imidazolin-2-one,1-(2-pentyl)-4-imidazolin-2-one, 1-phenyl-4-imidazolin-2-one,1-(4-fluorophenyl)-4-imidazolin-2-one,1-(3-methoxyphenyl)-4-imidazolin-2-one,1-(2-methylphenyl)-4-imidazolin-2-one, 1-benzyl-4-imidazolin-2-one,1-(3-chlorobenzyl)-4-imidazolin-2-one,1-(4-ethylbenzyl-4-imidazolin-2-one yields, respectively:

(±)-8-fluoro-5-(4-fluorophenyl)-2-[4-(3-methyl-4-imidazolin-2-on-1-yl)-1-butyl]-2,3,4,4a,5,9b-hexahydro-4a,9b-trans-1H-pyrido[4,3-b]indole;

(±)-8-fluoro-5-(4-fluorophenyl)-2-[[4-[3-(2-pentyl)-4-imidazolin-2-on-1-yl]-1-butyl]]-2,3,4,4a,5,9b-hexahydro-4a,9b-trans-1H-pyrido[4,3-b]indole;

(±)-8-fluoro-5-(4-fluorophenyl)-2-[4-(3-phenyl-4-imidazolin-2-on-1-yl)-1-butyl]-2,3,4,4a,5,9b-hexahydro-4a,9b-trans-1H-pyrido[4,3-b]indole;

(±)-8-fluoro-5-(4-fluorophenyl)-2-[[4-[3-(4-fluorophenyl)-4-imidazolin-2-on-1-yl]-1-butyl]]-2,3,4,4a,5,9b-hexahydro-4a,9b-trans-1H-pyrido[4,3-b]indole;

(±)-8-fluoro-5-(4-fluorophenyl)-2-[[4-[3-(3-methoxyphenyl)-4-imidazolin-2-on-1-yl]-1-butyl]]-2,3,4,4a,5,9b-hexahydro-4a,9b-trans-1H-pyrido[4,3-b]indole;

(±)-8-fluoro-5-(4-fluorophenyl)-2-[[4-[3-(2-methylphenyl)-4-imidazolin-2-on-1-yl]-1-butyl]]-2,3,4,4a,5,9b-hexahydro-4a,9b-trans-1H-pyrido[4,3-b]indole;

(±)-8-fluoro-5-(4-fluorophenyl)-2-[4-(3-benzyl-4-imidazolin-2-on-1-yl)-1-butyl]-2,3,4,4a,5,9b-hexahydro-4a,9b-trans-1H-pyrido[4,3-b]indole;

(±)-8-fluoro-5-(4-fluorophenyl)-2-[[4-[3-(3-chlorobenzyl)-4-imidazolin-2-on-1-yl]-1-butyl]]-2,3,4,4a,5,9b-hexahydro-4a,9b-trans-1H-pyrido[4,3-b]indole;

(±)-8-fluoro-5-(4-fluorophenyl)-2-[[4-[3-(4-ethylbenzyl)-4-imidazolin-2-on-1-yl]-1-butyl]]-2,3,4,4a,5,9b-hexahydro-4a,9b-trans-1H-pyrido[4,3-b]indole;and

(±)-8-fluoro-5-(4-fluorophenyl)-2-[4-(3-methylimidazolin-5-on-1-yl)-1-butyl]-2,3,4,4a,5,9b-hexahydro-4a,9b-trans-1H-pyrido[4,3-b]indole.

In like manner, 2-imidazolidinone, 1-methyl-2-imidazolidinone,4-methyl-2-piperazinone, perhydro-2-pyrimidinone,2,3-dihydrobenz[d]imidazol-2-one (tautomeric equivalent of2-hydroxybenz[d]imidazole) and 4-oxazolidinone are converted,respectively, to:

(±)-8-fluoro-5-(4-fluorophenyl)-2-[4-(2-imidazolinon-1-yl)-1-butyl]-2,3,4,4a,5,9b-hexahydro-4a,9b-trans-1H-pyrido[4,3-b]indole;

(±)-8-fluoro-5-(4-fluorophenyl)-2-[4-(3-methyl-2-imidazolinon-1-yl)-1-butyl]-2,3,4,4a,5,9b-hexahydro-4a,9b-trans-1H-pyrido[4,3-b]indole;

(±)-8-fluoro-5-(4-fluorophenyl)-2-[4-(4-methyl-2-piperazinon-1-yl)-1-butyl]-2,3,4,4a,5,9b-hexahydro-4a,9b-trans-1H-pyrido[4,3-b]indole;

(±)-8-fluoro-5-(4-fluorophenyl)-2-[4-(perhydro-2-pyrimidinon-1-yl)-1-butyl]-2,3,4,4a,5,9b-hexahydro-4a,9b-trans-1H-pyrido[4,3-b]indole;

(±)-8-fluoro-5-(4-fluorophenyl)-2-[4-(2,3-dihydrobenz[d]imidazol-2-on-1-yl)-1-butyl]-2,3,4,4a,5,9b-hexahydro-4a,9b-trans-1H-pyrido[4,3-b]indole;and

(±)-8-fluoro-5-(4-fluorophenyl)-2-[4-(oxazolidin-4-on-3-yl)-1-butyl]-2,3,4,4a,5,9b-hexahydro-4a,9b-trans-1H-pyrido[4,3-b]indole.

EXAMPLE 23 2-(4-Acetylpiperazino)ethanol

2-Piperazinoethanol (7.81 g, 60 mmoles) and triethylamine (8.36 ml, 66mmoles) were dissolved in 100 ml of methylene chloride and cooled to0°-5° C. Acetyl chloride (4.28 ml, 60 mmoles) in 20 ml of methylenechloride was added and the reaction mixture warmed to room temperature,held for 2 hours, and then evaporated in vacuo to dry solids. The solidswere triturated with four portions of warm ether. The triturates werecombined, dried over anhydrous magnesium sulfate, filtered andevaporated to yield 2-(4-acetylpiperazino)ethanol as an oil [7.5 g; freeof triethylamine and triethylamine hydrochloride by pnmr assay; Rf 0.3(methanol/10% acetic acid)].

In this process acetyl chloride is replaced by an equivalent ofacetoformic acid reagent [cf Blackwood et al., J. Am. Chem. Soc. 82, pp.5194-7 (1960)], isobutyryl chloride, valeryl chloride, benzoyl chloride,4-methoxybenzoyl chloride, phenylacetyl chloride, 3-fluorophenylacetylchloride, methanesulfonyl chloride, benzenesulfonyl chloride,p-toluenesulfonyl chloride, or 4-chlorobenzenesulfonyl chloride toproduce, respectively,

2-(4-formylpiperazino)ethanol;

2-(4-isobutyrylpiperazino)ethanol;

2-(4-valerylpiperazino)ethanol;

2-(4-benzoylpiperazino)ethanol;

2-[4-(4-methoxybenzoyl)piperazino]ethanol;

2-(4-phenylacetylpiperazino)ethanol;

2-[4-(3-chlorophenylacetyl)piperazino]ethanol;

2-(4-methanesulfonylpiperazino)ethanol;

2-(4-benzenesulfonylpiperazino)ethanol;

2-[4-(p-toluenesulfonyl)piperazino]ethanol; and

2-[4-(4-chlorobenzenesulfonyl)piperazino]ethanol.

In the same process, 2-piperazinoethanol is replaced by a large excessof piperazine (e.g., 5 equivalents) and triethylamine is omitted toproduce 1-acetylpiperazine.

In the same process, 2-piperazinoethanol is replaced by equivalent2-(4-acetylpiperazino)ethanol and acetyl chloride is replaced byequivalent methanesulfonyl chloride to produce2-(4-acetylpiperazino)ethyl mesylate.

EXAMPLE 24 2-(4-Acetylpiperazino)ethyl Chloride Method A

2-(4-Acetylpiperazino)ethanol (30 g) was dissolved in 30 ml of methylenechloride and cooled to 0°-5° C. Excess thionyl chloride (10 ml) wasadded dropwise. Precipitation of some gum and solids was noted. Thereaction mixture was then refluxed for 90 minutes by which time theprecipitated materials had redissolved. The mixture was evaporated todryness in vacuo. The resulting gum was taken up in 100 ml of acetoneand insolubles removed by filtration. The acetone filtrate wasevaporated to an oil which was crystallized from 1:2 ethanol:ethylacetate and ether to yield purified 2-(4-acetylpiperazino)ethylchloride.

In like manner, the other acylpiperazinoethanols of the precedingExample are converted to:

2-(4-formylpiperazino)ethyl chloride;

2-(4-isobutyrylpiperazino)ethyl chloride;

2-(4-valerylpiperazino)ethyl chloride;

2-(4-benzoylpiperazino)ethyl chloride;

2-[4-(4-methoxybenzoyl)piperazino]ethyl chloride;

2-(4-phenylacetylpiperazino)ethyl chloride;

2-[4-(3-chlorophenylacetyl)piperazino]ethyl chloride;

2-(4-methanesulfonylpiperazino)ethyl chloride;

2-(4-benzenesulfonylpiperazino)ethyl chloride;

2-[4-(p-toluenesulfonyl)piperazino]ethyl chloride; and

2-[4-(4-chlorobenzenesulfonyl)piperazino]ethyl chloride.

Method B

1-Acetylpiperazine (1.28 g, 10 mmoles), 1,2-dichloroethane (5 g, 50mmoles), anhydrous sodium carbonate (2.5 g) and potassium iodide (25 mg)are combined in 40 ml of 3-methyl-2-butanone and refluxed for 16 hours.The reaction mixture is evaporated to dryness in vacuo and the residuedistributed between 100 ml of water and 150 ml of methylene chloride.The methylene chloride layer is dried over anhydrous magnesium sulfateand evaporated to dryness to yield 2-(4-acetylpiperazino)-ethylchloride.

In this process, substitution of 1,2-dichloroethane by1,2-dibromoethane, 1,3-dichloropropane, 1,4-dibromobutane,1-bromo-4-chlorobutane, 1,5-dibromopentane or 1,6-dibromohexane providesa method for the preparation of, respectively:

2-(4-acetylpiperazino)ethyl bromide;

3-(4-acetylpiperazino)propyl chloride;

4-(4-acetylpiperazino)butyl bromide;

4-(4-acetylpiperazino)butyl chloride;

5-(4-acetylpiperazino)pentyl bromide; and

6-(4-acetylpiperazino)hexyl bromide.

EXAMPLE 25(±)-8-Fluoro-5-(4-fluorophenyl)-2-[2-(4-acetylpiperazino)-ethyl]-2,3,4,4a,5,9b-hexahydro-4a,9b-trans-1H-pyrido[4,3-b]-indoleBis-hydrogen Maleate

(±)-8-Fluoro-5-(4-fluorophenyl)-2,3,4,4a,5,9b-hexahydro-4a,9b-trans-1H-pyrido[4,3-b]indole(1.00 g, 3.50 mmole), 2-(4-acetylpiperazino)ethyl chloride (0.885 g,3.90 mmole) and triethylamine (1.09 ml, 7.80 mmole) were combined in 75ml of absolute ethanol and refluxed for 2 hours. The reaction mixturewas then cooled to room temperature and evaporated to dryness in vacuo.The residue was distributed between water and ether and the water layerextracted with two portions of fresh ether. The combined ether layerswere dried over anhydrous magnesium sulfate filtered and evaporated toyield a first crop of product. The earlier aqueous phase was made basicwith 10% sodium hydroxide and extracted with two portions of freshether. The combined, dried ether extracts were likewise taken to drynessto yield a second crop of product, pumped under high vacuum to removeextraneous triethylamine. The first and second crops of product werecombined and chromatographed on 30 g of silica gel with 1:1 ethylacetate:methanol as eluant.

Clean product fractions were combined and evaporated to yield the titleproduct as the free base (gum). The free base was taken into acetone andexcess maleic acid added. The title product crystallized in two crops,which were combined and recrystallized from acetonitrile/methanol.Yield: 428 mg (m.p. 203.5°-204.5° C.; m/e 440).

Analysis: Calcd. for C₂₅ H₃₀ ON₄ F₂.2C₄ H₄ O₄ : C, 58.92; H, 5.69; N,8.33. Found: C, 58.32; H, 5.60; N, 8.16.

In like manner, 2-(4-acetylpiperazino)ethyl bromide and2-(4-acetylpiperazino)ethyl mesylate are reacted with the samepyridoindole substrate to produce the title product.

The same process, substituting 2-(4-acetylpiperazino)-ethyl chloridewith the appropriate chloride or bromide of the preceding Example, isused to prepare:

(±)-8-fluoro-5-(4-fluorophenyl)-2-[2-(4-formylpiperazino)ethyl]-2,3,4,4a,5,9b-hexahydro-4a,9b-trans-1H-pyrido[4,3-b]indole;

(±)-8-fluoro-5-(4-fluorophenyl)-2-[2-(4-isobutyrylpiperazino)ethyl]-2,3,4,4a,5,9b-hexahydro-4a,9b-trans-1H-pyrido[4,3-b]indole;

(±)-8-fluoro-5-(4-fluorophenyl)-2-[2-(4-valerylpiperazino)ethyl]-2,3,4,4a,5,9b-hexahydro-4a,9b-trans-1H-pyrido[4,3-b]indole;

(±)-8-fluoro-5-(4-fluorophenyl)-2-[2-(4-benzoylpiperazino)ethyl]-2,3,4,4a,5,9b-hexahydro-4a,9b-trans-1H-pyrido[4,3-b]indole;

(±)-8-fluoro-5-(4-fluorophenyl)-2-[[2-[4-(4-methoxybenzoyl)piperazino]ethyl]]-2,3,4,4a,5,9b-hexahydro-4a,9b-trans-1H-pyrido[4,3-b]indole;

(±)-8-fluoro-5-(4-fluorophenyl)-2-[2-(4-phenylacetylpiperazino)ethyl]-2,3,4,4a,5,9b-hexahydro-4a,9b-trans-1H-pyrido[4,3-b]indole;

(±)-8-fluoro-5-(4-fluorophenyl)-2-[[2-[4-(3-chlorophenylacetyl)piperazino]ethyl]]-2,3,4,4a,5,9b-hexahydro-4a,9b-trans-1H-pyrido[4,3-b]indole;

(±)-8-fluoro-5-(4-fluorophenyl)-2-[3-(4-acetylpiperazino)-1-propyl]-2,3,4,4a,5,9b-hexahydro-4a,9b-trans-1H-pyrido[4,3-b]indole;

(±)-8-fluoro-5-(4-fluorophenyl)-2-[4-(4-acetylpiperazino)-1-butyl]-2,3,4,4a,5,9b-hexahydro-4a,9b-trans-1H-pyrido[4,3-b]indole;

(±)-8-fluoro-5-(4-fluorophenyl)-2-[5-(4-acetylpiperazino)-1-pentyl]-2,3,4,4a,5,9b-hexahydro-4a,9b-trans-1H-pyrido[4,3-b]indole;

(±)-8-fluoro-5-(4-fluorophenyl)-2-[6-(4-acetylpiperazino)-1-hexyl]-2,3,4,4a,5,9b-hexahydro-4a,9b-trans-1H-pyrido[4,3-b]indole;

(±)-8-fluoro-5-(4-fluorophenyl)-2-[2-(4-methanesulfonylpiperazino)ethyl]-2,3,4,4a,5,9b-hexahydro-4a,9b-trans-1H-pyrido[4,3-b]indole;

(±)-8-fluoro-5-(4-fluorophenyl)-2-[2-(4-benzenesulfonylpiperazino)ethyl]-2,3,4,4a,5,9b-hexahydro-4a,9b-trans-1H-pyrido[4,3-b]indole;

(±)-8-fluoro-5-(4-fluorophenyl)-2-[[2-[4(p-toluenesulfonyl)piperazino)ethyl]]-2,3,4,4a,5,9b-hexahydro-4a,9b-trans-1H-pyrido[4,3-b]indole;and

(±)-8-fluoro-5-(4-fluorophenyl)-2-[[2-[4(4-chlorobenzenesulfonyl)piperazino]ethyl]]-2,3,4,4a,5,9b-hexahydro-4a,9b-trans-1H-pyrido[4,3-b]indole.

The same process, substituting the appropriate phenylpyridoindole forthe difluorophenylpyridoindole, is used to prepare:

(±)-5-phenyl-2[2-(4-acetylpiperazino)ethyl]-2,3,4-4a,5,9b-hexahydro-4a,9b-trans-1H-pyrido[4,3-b]indole;

(±)-8-chloro-5-(4-chlorophenyl)-2-[2-(4-acetylpiperazino)ethyl]-2,3,4,4a,5,9b-hexahydro-4a,9b-trans-1H-pyrido[4,3-b]indole;

(±)-8-fluoro-5-(3-methoxyphenyl)-2-[2-(4-acetylpiperazino)ethyl]-2,3,4,4a,5,9b-hexahydro-4a,9b-trans-1H-pyrido[4,3-b]indole;and

(±)-8-methyl-5-(3,4-dimethylphenyl)-2-[2-(4-acetylpiperazino)ethyl]-2,3,4,4a,5,9b-hexahydro-4a,9b-trans-1H-pyrido[4,3-b]indole.

EXAMPLE 26(+)-8-Fluoro-5-(4-fluorophenyl)-2-[2-(4-acetylpiperazino)ethyl]-2,3,4,4a,5,9b-hexahydro-4a,9b-trans-1H-pyrido[4,3-b]indoleBis-hydrogen Maleate

(+)-8-Fluoro-5-(4-fluorophenyl)-2,3,4,4a,5,9b-hexahydro-4a,9b-trans-pyrido[4,3-b]indolehydrochloride (526 mg, 1.63 mmole) was converted to free base accordingto the method of Example 3 and combined with 2-(4-acetylpiperazino)ethylchloride (407 mg, 1.80 mmole) and triethylamine (0.50 ml, 3.6 mmole) in40 ml of absolute ethanol. Following 3 hours of reflux, the titleproduct was recovered, purified, converted to the salt form andrecrystallized according to the procedure of the preceding Example.Yield: 340 mg [m.p. 195°-196° C., [alpha]_(D) ²⁵ =+10.6 (c=0.5,methanol), m/e 440].

Analysis: Calcd. for C₂₅ H₃₀ N₄ OF₂.2C₄ H₄ O₄ : C, 58.92; H, 5.69; N,8.33. Found: C, 58.47; H, 5.44; N, 8.20.

EXAMPLE 27 1-Benzyl-4-(4-chlorobutyryl)piperazine

N-Benzylpiperazine (1.0 g, 5.7 mmole) and triethylamine (1.17 ml, 8.5mmole) were combined in 20 ml of methylene chloride. 4-Chlorovalerylchloride (0.945 ml, 8.5 mmole) in 10 ml of methylene chloride was addeddropwise over 20 minutes and the reaction mixture stirred for 16 hoursat room temperature. Water (20 ml) was then added and the organic layerdried (anhydrous magnesium sulfate) and evaporated in vacuo to a gum.The gum was chromatographed on silica gel with ethyl acetate as eluantand tlc monitoring. Clean product fractions were combined and evaporatedto yield the title product as a gum [920 mg, Rf 0.5 (ethyl acetate)].

Triethylamine is not essential to this acylation. If omitted, excessbase is added to the aqueous quench.

In like manner, substituting the appropriate chloroacyl chloride for4-chlorobutyryl chloride, the following compounds are prepared:

1-benzyl-4-(2-chloroacetyl)piperazine;

1-benzyl-4-(3-chloropropionyl)piperazine;

1-benzyl-4-(5-chlorovaleryl)piperazine; and

1-benzyl-4-(6-chlorohexanoyl)piperazine.

In like manner, substituting the appropriate N-substituted piperazinefor 1-benzylpiperazine, the folliwng compounds are prepared:

1-(4-chlorobutyryl)-4-phenylpiperazine;

1-(4-chlorobutyryl)-4-methylpiperazine;

1-(4-chlorobutyryl)-4-isopropylpiperazine;

1-(4-chlorobutyryl)-4-(4-methylphenyl)piperazine;

1-acetyl-4-(4-chlorobutyryl)piperazine;

1-(4-chlorobutyryl)4-(4-methoxybenzoyl)piperazine;

1-(3-bromobenzoyl)-4-(4-chlorobutyryl)-piperazine;

1-(4-chlorobutyryl)-4-(2-fluorobenzoyl)piperazine; and

1-(4-chlorobutyryl)-4-(3-chloro-4-ethylbenzoyl)-piperazine.

EXAMPLE 28(±)-(8-Fluoro-5-(4-fluorophenyl)-2-[3-(4-benzylpiperazinocarbonyl)-1-propyl]-2,3,4,4a,5,9b-hexahydro-4a,9b-trans-1H-pyrido[4,3-b]indoleBis-hydrochloride

By the methods of Example 2,(±)-8-fluoro-5-(4-fluorophenyl)-2,3,4,4a,5,9b-hexahydro-4a,9b-trans-1H-pyrido[4,3-b]indole(625 mg, 2.2 mmole) was reacted with1-benzyl-4-(4-chlorobutyryl)piperazine to yield chromatographed freebase form of the title product. The base was taken into acetone,converted to the bis-hydrochloride with excess ethereal hydrogenchloride, and the title product isolated by evaporation to dryness andrepulp in ether [0.485 g, m/e 530].

Analysis: Calcd. for C₃₂ H₃₆ ON₄ F₂.2HCl.2.25 H₂ O: C, 59.67; H, 6.52;N, 8.69. Found: C, 59.55; H, 6.53; N, 8.68.

In like manner, substituting an equivalent amount of the appropriateorganic chloride of the preceding Example for thechlorobutyrylpiperazine, the following compounds are prepared:

(±)-8-fluoro-5-(4-fluorophenyl)-2-[1-(4-benzylpiperazinocarbonyl)methyl]-2,3,4,4a,5,9b-hexahydro-4a,9b-trans-1H-pyrido[4,3-b]indole;

(±)-8-fluoro-5-(4-fluorophenyl)-2-[2-(4-benzylpiperazinocarbonyl)ethyl]-2,3,4,4a,5,9b-hexahydro-4a,9b-trans-1H-pyrido[4,3-b]indole;

(±)-8-fluoro-5-(4-fluorophenyl)-2-[4-benzylpiperazinocarbonyl)butyl]-2,3,4,4a,5,9b-hexahydro-4a,9b-trans-1H-pyrido[4,3-b]indole;

(±)-8-fluoro-5-(4-fluorophenyl)-2-[5-(4-benzylpiperazinocarbonyl)pentyl]-2,3,4,4a,5,9b-hexahydro-4a,9b-trans-1H-pyrido[4,3-b]indole;

(±)-8-fluoro-5-(4-fluorophenyl)-2-[3-(4-phenylpiperazinocarbonyl)-1-propyl]-2,3,4,4a,5,9b-hexahydro-4a,9b-trans-1H-pyrido[4,3-b]indole;

(±)-8-fluoro-5-(4-fluorophenyl)-2-[3-(4-methylpiperazinocarbonyl)-1-propyl]-2,3,4,4a,5,9b-hexahydro-4a,9b-trans-1H-pyrido[4,3-b]indole;

(±)-8-fluoro-5-(4-fluorophenyl)-2-[3-(4-isopropylpiperazinocarbonyl)-1-propyl]-2,3,4,4a,5,9b-hexahydro-4a,9b-trans-1H-pyrido[4,3-b]indole;

(±)-8-fluoro-5-(4-fluorophenyl)-2-[[3-[4-(4-methylphenyl)piperazinocarbonyl]-1-propyl]]-2,3,4,4a,5,9b-hexahydro-4a,9b-trans-1H-pyrido[4,3-b]indole;

(±)-8-fluoro-5-(4-fluorophenyl)-2-[3-(4-acetylpiperazinocarbonyl)-1-propyl]-2,3,4,4a,5,9b-hexahydro-4a,9b-trans-1H-pyrido[4,3-b]indole;

(±)-8-fluoro-5-(4-fluorophenyl)-2-[[3-[4-(4-methoxybenzoyl)piperazinocarbonyl]-1-propyl]]-2,3,4,4a,5,9b-hexahydro-4a,9b-trans-1H-pyrido[4,3-b]indole;

(±)-8-fluoro-5-(4-fluorophenyl)-2-[[3-[4-(3-bromobenzoyl)piperazinocarbonyl]-1-propyl]]-2,3,4,4a,5,9b-hexahydro-4a,9b-trans-1H-pyrido[4,3-b]indole;

(±)-8-fluoro-5-(4-fluorophenyl)-2-[[3-[4-(2-fluorobenzoyl)piperazinocarbonyl]-1-propyl]]-2,3,4,4a,5,9b-hexahydro-4a,9b-trans-1H-pyrido[4,3-b]indole;and

(±)-8-fluoro-5-(4-fluorophenyl)-2-[[3-[4-(3-chloro-2-ethylbenzoyl)piperazinocarbonyl]-1-propyl]]-2,3,4,4a,5,9b-hexahydro-4a,9b-trans-1H-pyrido[4,3-b]indole.

EXAMPLE 29(±)-8-Fluoro-5-(4-fluorophenyl)-2-[4-(4-benzylpiperazino)-1-butyl)]-2,3,4,4a,5,9b-hexahydro-4a,9b-trans-1H-pyrido-[4,3-b]indoleTris-hydrochloride

(±)-8-Fluoro-5-(4-fluorophenyl)-2-[3-(4-benzylpiperazinocarbonyl)-1-propyl]-2,3,4,4a,5,9b-hexahydro-4a,9b-trans-1H-pyrido[4,3-b]indolebis-hydrochloride (1 g) was taken into 30 ml of tetrahydrofuran. Lithiumaluminum hydride (about 9 equivalents) was added portionwise; evolutionof hydrogen was noted during most of the addition. After stirring for anadditional 30 minutes at room temperature, an excess of Glauber's salt(sodium sulfate decahydrate) was added and the mixture stirred for anadditional 10 minutes. The reaction mixture was filtered withtetrahydrofuran wash and the combined filtrate and washes evaporated todryness. The resulting gum was taken up in acetone and converted to thehydrochloride salt by the addition of ethereal hydrogen chloride. Theresulting slurry was taken to dryness, repulped in a mixture of 30 ml ofacetone and 10 ml of methanol, and filtered to yield the title product[120 mg, Rf 0.2 (methanol); m/e 516].

Analysis: Calcd. for C₃₂ H₃₈ N₄ F₂.3HCl C, 61.39; H, 6.59; N, 8.95.Found: C, 61.26; H, 6.68; N, 8.78.

In like manner, employing sufficient lithium aluminum hydride to reactwith acid protons, if present, and one or two amide functions aspresent, the other amides and bis-amides of the preceding Example arereduced to:

(±)-8-fluoro-5-(4-fluorophenyl)-2-[2-(4-benzylpiperazino)ethyl]-2,3,4,4a,5,9b-hexahydro-4a,9b-trans-1H-pyrido-[4,3-b]indole;

(±)-8-fluoro-5-(4-fluorophenyl)-2-[3-(4-benzylpiperazino)-1-propyl]-2,3,4,4a,5,9b-hexahydro-4a,9b-trans-1H-pyrido[4,3-b]indole;

(±)-8-fluoro-5-(4-fluorophenyl)-2-[5-(4-benzylpiperazino)-1-pentyl]-2,3,4,4a,5,9b-hexahydro-4a,9-b-trans-1H-pyrido[4,3-b]indole;

(±)-8-fluoro-5-(4-fluorophenyl)-2-[6-(4-benzylpiperazino)-1-hexyl]-2,3,4,4a,5,9b-hexahydro-4a,9b-trans-1H-pyrido[4,3-b]indole;

(±)-8-fluoro-5-(4-fluorophenyl)-2-[4-(4-phenylpiperazino)-1-butyl]-2,3,4,4a,5,9b-hexahydro-4a,9b-trans-1H-pyrido[4,3-b]indole;

(±)-8-fluoro-5-(4-fluorophenyl)-2-[4-(4-methylpiperazino)-1-butyl]-2,3,4,4a,5,9b-hexahydro-4a,9b-trans-1H-pyrido[4,3-b]indole;

(±)-8-fluoro-5-(4-fluorophenyl)-2-[4-(4-isopropylpiperazino)-1-butyl]-2,3,4,4a,5,9b-hexahydro-4a,9b-trans-1H-pyrido[4,3-b]indole;

(±)-8-fluoro-5-(4-fluorophenyl)-2-[4-(4-ethylpiperazino)-1-butyl]-2,3,4,4a,5,9b-hexahydro-4a,9b-trans-1H-pyrido[4,3-b]indole;

(±)-8-fluoro-5-(4-fluorophenyl)-2-[[4-[4-(4-methoxybenzyl)piperazino]-1-butyl]]-2,3,4,4a,5,9b-hexahydro-4a,9b-trans-1H-pyrido[4,3-b]indole;

(±)-8-fluoro-5-(4-fluorophenyl)-2-[[4-[4-(3-bromobenzyl)piperazino]-1-butyl]]-2,3,4,4a,5,9b-hexahydro-4a,9b-trans-1H-pyrido[4,3-b]indole;

(±)-8-fluoro-5-(4-fluorophenyl)-2-[[4-[4-(2-fluorobenzyl)piperazino]-1-butyl]]-2,3,4,4a,5,9b-hexahydro-4a,9b-trans-1H-pyrido[4,3-b]indoleand;

(±)-8-fluoro-5-(4-fluorophenyl)-2-[[4-[4-(3-chloro-2-ethylbenzyl)piperazino]-1-butyl]]-2,3,4,4a,5,9b-hexahydro-4a,9b-trans-1H-pyrido[4,3-b]indole.

EXAMPLE 30(±)-8-Fluoro-5-(4-fluorophenyl)-2-(4-piperazino-1-butyl)-2,3,4,4a,5,9b-hexahydro-4a,9b-trans-1H-pyrido[4,3-b]indoleTris-hydrochloride

The entire batch of(±)-8-fluoro-5-(4-fluorophenyl)-2-[4-(4-benzylpiperazino)-1-butyl]-2,3,4,4a,5,9b-hexahydro-4a,9b-trans-1H-pyrido[4,3-b]indoletris-hydrochloride from the preceding Example was taken into 10 ml ofethanol containing 3 drops of concentrated hydrochloric acid.Hydrogenation catalyst (10% Pd/C, 250 mg) was added and the mixturehydrogenated for 6 hours at 50 psi and 40° C. The catalyst was recoveredby filtration with ethanol wash. The combined filtrate and washes wereevaporated to a gum. The gum dissolved in the minimum methanol and wascrystallized by adding 100 ml of acetone and stirring for 30 minutes.The yield of title product as a trihydrate was 0.3 g (m.p. 229°-232°C.).

In the same manner, the other benzyl derivatives of the precedingExample are hydrogenolyzed to:

(±)-8-fluoro-5-(4-fluorophenyl)-2-(2-piperazinoethyl)-2,3,4,4a,5,9b-hexahydro-4a,9b-trans-1H-pyrido[4,3-b]indole;

(±)-8-fluoro-5-(4-fluorophenyl)-2-(3-piperazino-1-propyl)-2,3,4,4a,5,9b-hexahydro-4a,9b-trans-1H-pyrido[4,3-b]indole;

(±)-8-fluoro-5-(4-fluorophenyl)-2-(5-piperazino-1-pentyl)-2,3,4,4a,5,9b-hexahydro-4a,9b-trans-1H-pyrido[4,3-b]indole;and

(±)-8-fluoro-5-(4-fluorophenyl)-2-(6-piperazino-1-hexyl)-2,3,4,4a,5,9b-hexahydro-4a,9b-trans-1H-pyrido[4,3-b]indole.

EXAMPLE 31(±)-8-Fluoro-5-(4-fluorophenyl)-2-[4-(4-acetylpiperazino)-1-butyl]-2,3,4,4a,5,9b-hexahydro-4a,9b-trans-1H-pyrido[4,3-b]indoleBis-hydrochloride

(±)-8-Fluoro-5-(4-fluorophenyl)-2-(4-piperazino-1-butyl)-2,3,4,4a,5,9b-hexahydro-4a,9b-trans-1H-pyrido[4,3-b]indoletris-hydrochloride trihydrate (377 mg, 0.64 mmole) and triethylamine(0.68 ml, 4.92 mmole) were taken up in 8 ml of methylene chloride.Acetyl chloride (0.055 ml, 0.77 mmole) in 4 ml of methylene chloride wasadded dropwise over 20 minutes and the mixture stirred overnight at roomtemperature. Water (12 ml) was then added to the reaction mixture. Theorganic layer was dried over anhydrous magnesium sulfate filtered andevaporated to a gum. The gum was taken up in ether, converted tohydrochloride salt by the addition of ethereal hydrogen chloride, themixture evaporated to dryness and the residue repulped in acetone, fromwhich the title product was obtained as a hygroscopic solid (150 mg).

Analysis: Calcd. for C₂₇ H₃₄ N₄ OF₂.2HCl.2H₂ O: C, 56.15; H, 6.92; N,9.69. Found: C, 56.31; H, 7.24; N, 9.75.

In like manner, the other piperazine derivatives of the precedingExample are acetylated to yield:

(±)-8-fluoro-5-(4-fluorophenyl)-2-[2-(4-acetylpiperazino)ethyl]-2,3,4,4a,5,9b-hexahydro-4a,9b-trans-1H-pyrido[4,3-b]indole;

(±)-8-fluoro-5-(4-fluorophenyl)-2-[3-(4-acetylpiperazino)-1-propyl]-2,3,4,4a,5,9b-hexahydro-4a,9b-trans-1H-pyrido[4,3-b]indole;

(±)-8-fluoro-5-(4-fluorophenyl)-2-[5-(4-acetylpiperazino)-1-pentyl]-2,3,4,4a,5,9b-hexahydro-4a,9b-trans-1H-pyrido[4,3-b]indole;and

(±)-8-fluoro-5-(4-fluorophenyl)-2-[6-(4-acetylpiperazino)-1-hexyl]-2,3,4,4a,5,9b-hexahydro-4a,9b-trans-1-H-pyrido[4,3-b]indole;

Substitution of acetyl chloride with the appropriate acyl chloride,alkyl chloroformate or sulfonyl chloride in this process is used toproduce:

(±)-8-fluoro-5-(4-fluorophenyl)-2-[2-(4-propionylpiperazino)ethyl]-2,3,4,4a,5,9-hexahydro-4a,9b-trans-1H-pyrido[4,3-b]indole;

(±)-8-fluoro-5-(4-fluorophenyl)-2-[2-(4-isovalerylpiperazino)ethyl]-2,3,4,4a,5,9b-hexahydro-4a,9b-trans-1H-pyrido[4,3-b]indole;

(±)-8-fluoro-5-(4-fluorophenyl)-2-[2-(4-benzoylpiperazino)ethyl]-2,3,4,4a,5,9b-hexahydro-4a,9b-trans-1H-pyrido[4,3-b]indole;

(±)-8-fluoro-5-(4-fluorophenyl)-2-[[2-[4-(4-methoxybenzoyl)piperazino]ethyl]]-2,3,4,4a,5,9b-hexahydro-4a,9b-trans-1H-pyrido[4,3-b]indole;

(±)-8-fluoro-5-(4-fluorophenyl)-2-[[2-[4-(4-ethylbenzoyl)piperazino]ethyl]]-2,3,4,4a,5,9b-hexahydro-4a,9b-trans-1H-pyrido[4,3-b]indole;

(±)-8-fluoro-5-(4-fluorophenyl)-2-[2-(4-phenylacetylpiperazino)ethyl]-2,3,4,4a,5,9b-hexahydro-4a,9b-trans-1H-pyrido[4,3-b]indole;

(±)-8-fluoro-5-(4-fluorophenyl)-2-[2-(4-ethoxycarbonylpiperazino)ethyl]-2,3,4,4a,5,9b-hexahydro-4a,9b-trans-1H-pyrido[4,3-b]indole;

(±)-8-fluoro-5-(4-fluorophenyl)-2-[2-(4-methanesulfonylpiperazino)ethyl]-2,3,4,4a,5,9b-hexahydro-4a,9b-trans-1H-pyrido[4,3-b]indole;

(±)-8-fluoro-5-(4-fluorophenyl)-2-[[2-[4-(3-methylphenyl)sulfonylpiperazino]ethyl]]-2,3,4,4a,5,9b-hexahydro-4a,9b-trans-1H-pyrido[4,3-b]indole.

Anhydrides can be substituted for acyl chlorides in the process.Acetoformic acid reagent [cf Blackwood et al, J. Am. Chem. Soc. 82, pp.5194-5197 (1960)] is substituted for acetyl chloride to produce:

(±)-8-fluoro-5-(4-fluorophenyl)-2-[2-(4-formylpiperazino)ethyl]-2,3,4,4a,5,9b-hexahydro-4a,9b-trans-1H-pyrido[4,3-b]indole.

EXAMPLE 32

(±)-8-Fluoro-5-(4-fluorophenyl)-2-(3-piperazinocarbonyl-1-propyl)-2,3,4,4a,5,9b-hexahydro-4a,9b-trans-1H-pyrido[4,3-b]indoleBis-hydrochloride

(±)-8-Fluoro-5-(4-fluorophenyl)-2-[3-(4-benzylpiperazinocarbonyl)-1-propyl]-2,3,4,4a,5,9b-hexahydro-4a,9b-trans-1H-pyrido[4,3-b]indolebis-hydrochloride from Example 28 (1 g) was hydrogenated in 20 ml ofethanol containing 6 drops of concentrated hydrochloric acid in thepresence of 300 mg of 10% Pd/C catalyst at 45 psi and 40° C. for 16hours. The catalyst was recovered by filtration and the mother liquorevaporated to a gum. The gum was crystallized by slurry with acetone[0.640 g; ir (KBr) 1470, 1508, 1639, 1733, 3390 Cm⁻¹ ; m/e 440].

Analysis: Calcd. for C₂₅ H₃₀ N₄ OF₂.2HCl.3H₂ O: C, 52.91; H, 6.69; N,9.87. Found: C, 52.61; H, 6.53; N, 9.93.

EXAMPLE 33(±)-8-Fluoro-5-(4-fluorophenyl)-2-(4-piperazino-1-butyl)-2,3,4,4a,5,9b-hexahydro-4a,9b-trans-1H-pyrido[4,3-b]indole

By the method of Example 29 employing about 10.5 equivalents of lithiumaluminum hydride, the piperazinocarbonyl compound of the precedingExample is reduced to the title product. The crude is converted totris-hydrochloride and purified according to Example 30.

EXAMPLE 34(±)-8-Fluoro-5-(4-fluorophenyl)-2-[3-(4-acetylpiperazinocarbonyl)-1-propyl]-2,3,4,4a,5,9b-hexahydro-4a,9b-trans-1H-pyrido[4,3-b]indoleHydrochloride

The piperazinocarbonyl compound of the twice preceding Example (500 mg,1.14 mmole), acetyl chloride (0.089 ml, 1.25 mmole) and triethylamine(0.628 ml, 4.5 mmole) in a total of 15 ml of methylene chloride werereacted by the methods of Example 31. The crude product (isolated fromthe methylene chloride after aqueous quench) was chromatographed onsilica gel with 1:1 methanol:ethyl acetate as eluant and tlc monitoring[Rf 0.2 (1:1 methanol:ethyl acetate)]. Clean product containingfractions were combined and evaporated to dryness. The resulting gum wastaken up in ether, converted to hydrochloride by the addition ofethereal hydrogen chloride and evaporated to solids. Repulp of thesolids in 10 ml of acetone and filtration gave the title product (50 mg,m.p. 220°-223° C.).

Analysis: Calcd. for C₂₇ H₃₂ N₄ O₂ F.HCl.0.75H₂ O: C, 60.90; H, 6.54; N,10.52. Found: C, 60.96; H, 6.44; N, 10.32.

The product of this Example is reduced with hydride to yield(±)-8-fluoro-5-(4-fluorophenyl)-2-[4-(3-ethylpiperazino)-1-butyl]-2,3,4,4a,5,9b-hexahydro-4a,9b-trans-1H-pyrido[4,3-b]indoleaccording to Example 29 above.

EXAMPLE 35(±)-8-Fluoro-5-(4-fluorophenyl)-2-[4-(4-acetylpiperazino)-1-butyl]-2,3,4,4a,5,9b-hexahydro-4a,9b-trans-1H-pyrido-[4,3-b]indoleBis-hydrochloride

(±)-8-Fluoro-5-(4-fluorophenyl)-2-(4-bromo-1-butyl)-2,3,4,4a,5,9b-hexahydro-4a,9b-trans-1H-pyrido[4,3-b]indoleof Example 8 is reacted with 5 equivalents of 1-acetylpiperazine inrefluxing ethanol according to Example 25. The reaction mixture isevaporated to dryness to yield the hydrobromide salt. The latter ispartitioned between aqueous sodium hydroxide and ether; the aqueouslayer is further extracted with ether. The combined ether layer andextracts are dried, evaporated to dryness and converted to title productaccording to Example 31.

By the same procedure, substituting 1-acetylpiperazine with 10equivalents of piperazine,(±)-8-fluoro-5-(4-fluorophenyl)-2-(4-piperazino-1-butyl)-2,3,4,4a,5,9b-hexahydro-4a,9b-trans-1H-pyrido[4,3-b]indoleis prepared by the same method.

Alternatively, the intermediate acyl derivative of Example 8 is reactedwith excess piperazine to yield(±)-8-fluoro-5-(4-fluorophenyl)-2-(3-piperazinocarbonyl-1-propyl)-2,3,4,4a,5,9b-hexahydro-4a,9b-trans-1H-pyrido[4,3-b]indole.The latter is reduced with lithium aluminum hydride according to Example29 and then acylated to yield the title product.

EXAMPLE 36(±)-8-Fluoro-5-(4-fluorophenyl)-2-[4-(4-acetylpiperazino)-1-butyl]-2,3,4,4a,5,9b-hexahydro-4a,9b-trans-1H-pyrido[4,3-b]indole

(±)-8-Fluoro-5-(4-fluorophenyl)-2-(4-amino-1-butyl)-2,3,4,4a,5,9b-hexahydro-4a,9b-trans-1H-pyrido[4,3-b]indolehydrochloride of Example 11 is converted to free base form in3-methyl-2-pentanone by partitioning between excess dilute sodiumhydroxide and the ketone solvent. The organic layer is separated, driedover anhydrous magnesium sulfate and filtered. An equimolar portion ofN,N-bis(2-chloroethyl)acetamide (derived from diethylamine byN-acetylation and conversion to the bis-chloride) and excess sodiumcarbonate are added to filtrate, and the mixture heated at 85° C. for 16hours. Evaporation of dryness yields the title product asbis-hydrochloride.

EXAMPLE 37 1-(4-Chloro-1-butyl)-2,3-indolinedione

Sodium hydride (50% dispersion in oil, 1.63 g, 34 mmole) under drynitrogen was washed with 50 ml of ether to remove the oil. The ether wasseparated by decantation. Dimethylformamide (25 ml) was added to theether wet sodium hydride. A solution of 2,3-indolinedione (isatin, 5 g,34 mmole) and 1,4-dichlorobutane (21.6 g, 18.6 ml, 0.17 mmole) in 200 mlof dimethylformamide was added dropwise over 1 hour, maintaining thetemperature at 25°-28° C. The resulting solution was stirred for 1 hourat room temperature. The reaction mixture was filtered, and the filtrateevaporated to 30 ml and diluted with 50 ml of methylene chloride. Theresulting mixture was again filtered, the filtrate evaporated to drynessand the residue slurried in 200 ml of ether. The ether was decanted froma drum and evaporated to yield the title product [830 mg, Rf 0.55 1:1ethyl acetate:hexane)].

By the same method 2-pyrroline-4,5-dione, 2,3-pyrrolidinedione and2,3-piperidinedione are converted, respectively, to1-(4-chloro-1-butyl)-2-pyrroline-4,5-dione,1-(4-chloro-1-butyl)-2,3-pyrrolidinedione and1-(4-chloro-1-butyl)-2,3-piperidinedione.

EXAMPLE 38(±)-8-Fluoro-5-(4-fluorophenyl)-2-[4-(2,3-indolinedion-1-yl)-1-butyl]-2,3,4,4a,5,9b-hexahydro-4a,9b-trans-1H-pyrido[4,3-b]indoleHydrochloride

1-(4-Chloro-1-butyl)-2,3-indolinedione (830 mg, 3.5 mmole),(±)-8-fluoro-5-(4-fluorophenyl)-2,2,3,4,4a,5,9b-hexahydro-4a,9b-trans-1H-pyrido[4,3-b]indole(500 mg, 1.75 mmole), anhydrous sodium carbonate (1.1 g, 10.4 mmole) andpotassium iodide (5 mg) were combined in 3-methyl-2-butanone (20 ml) andrefluxed for 16 hours. The reaction mixture was evaporated to drynessand the residue partitioned between 50 ml of methylene chloride and 50ml of water. The aqueous phase was washed with 50 ml additionalmethylene chloride. The organic layers were combined, dried overanhydrous magnesium sulfate, filtered and evaporated to a gum. The gumwas chromatographed on silica gel using ethyl acetate and monitoring bytlc. Clean product containing fractions were combined and evaporated todryness. The residue was triturated with ethereal hydrogen chloride toyield the title product [226 mg; ir (KBr) 1477, 1520, 1623, 1724, 3390cm⁻¹ ].

By the same method, the other 4-chloro-1-butyl compounds of thepreceding Example are converted to:

(±)-8-fluoro-5-(4-fluorophenyl)-2-[4-(2-pyrroline-4,5-dion-1-yl)-1-butyl]-2,3,4,4a,5,9b-hexahydro-4a,9b-trans-1H-pyrido[4,3-b]indole;

(±)-8-fluoro-5-(4-fluorophenyl)-2-[4-(pyrrolidine-2,3-dion-1-yl)-1-butyl]-2,3,4,4a,5,9b-hexahydro-4a,9b-trans-1H-pyrido[4,3-b]indole;and

(±)-8-fluoro-5-(4-fluorophenyl)-2-[4-(piperidine-2,3-dion-1-yl)-1-butyl]-2,3,4,4a,5,9b-hexahydro-4a,9b-trans-1H-pyrido[4,3-b[indole.

By the same method, substituting the appropriately substitutedpyrido[4,3-bindole for the difluoropyrido[4,3-b]indole, the followingcompounds are prepared:

(+)-8-fluoro-5-(4-fluorophenyl)-2-[4-(indoline-2,3-dion-1-yl)-1-butyl]-2,3,4,4a,5,9b-hexahydro-4a,9b-trans-1H-pyrido[4,3-b]indole;

(±)-8-fluoro-5-(3,4-difluorophenyl)-2-[4-(indoline-2,3-dion-1-yl)-1-butyl]-2,3,4,4a,5,9b-hexahydro-4a,9b-trans-1H-pyrido[4,3-b]indole;

(±)-8-chloro-5-phenyl-2-[4-(indoline-2,3-dion-1-yl)-1-butyl]-2,3,4,4a,5,9b-hexahydro-4a,9b-trans-1H-pyrido[4,3-b]indole;and

(±)-8-methyl-5-(4-methylphenyl)-2-[4-(indoline-2,3-dion-1-yl)-1-butyl]-2,3,4,4a,5,9b-hexahydro-4a,9b-trans-1H-pyrido[4,3-b]indole

EXAMPLE 39(±)-8-Fluoro-5-(4-fluorophenyl)-2-[4-(1,3-dioxolan-2-yl)-1-butyl]-2,3,4,4a,5,9b-hexahydro-4a,9b-trans-1H-pyrido[4,3-b]indole

By the procedure of Example 37,(±)-8-fluoro-5-(4-fluorophenyl)-2,2,3,4,4a,5,9b-hexahydro-4a,9b-trans-1H-pyrido[4,3-b]indoleis reacted with 2-(4-chloro-1-butyl)-2,3-dioxolane (the ethyleneglycolacetal of 5-chlorovaleraldehyde) to yield the title product.

By the same method, 2-(2-bromo-1-ethyl)-2,3-dioxolane,2-(3-mesyloxy-1-propyl)-2,3-dioxolane and2-(5-iodo-1-pentyl)-2,3-dioxolane are reacted to produce, respectively:

(±)-8-fluoro-5-(4-fluorophenyl)-2-[2-(1,3-dioxalan-2-yl)-1-ethyl]-2,3,4,4a,5,9b-hexahydro-4a,9b-trans-1H-pyrido[4,3-b]indole;

(±)-8-fluoro-5-(4-fluorophenyl)-2-[3-(1,3-dioxolan-2-yl)-1-propyl]-2,3,4,4a,5,9b-hexahydro-4a,9b-trans-1H-pyrido[4,3-b]indole;and

(±)-8-fluoro-5-(4-fluorophenyl)-2-[5-(1,3-dioxolan-2-yl)-1-pentyl]-2,3,4,4a,5,9b-hexahydro-4a,9b-trans-1H-pyrido[4,3-b]indole.

EXAMPLE 40(±)-8-Fluoro-5-(4-fluorophenyl)-2-(5-oxo-1-pentyl)-2,3,4,4a,5,9b-hexahydro-4a,9b-trans-1H-pyrido[4,3-b]indole

Acetal from the preceding Example (1 g) is heated to 40°-45° C. in amixture of 10 ml of 1 N hydrochloric acid and 10 ml of water for 4hours. The methanol is removed in vacuo and the aqueous residue madebasic with 5% sodium bicarbonate. The mixture is extracted with two 15ml portions of methylene chloride. The organic extracts are combined,dried over anhydrous sodium sulfate, filtered and evaporated to yieldthe title product. Alternatively, dilute acid is introduced into thework-up stage of the preceding Example, and the title product isolateddirectly without isolation of the intermediate acetal.

By the same method, the other acetals of the preceding Example areconverted to:

(±)-8-fluoro-5-(4-fluorophenyl)-2-(3-oxo-1-propyl)-2,3,4,4a,5,9b-hexahydro-4a,9b-trans-1H-pyrido[4,3-b]indole;

(±)-8-fluoro-5-(4-fluorophenyl)-2-(4-oxo-1-butyl)-2,3,4,4a,5,9b-hexahydro-4a,9b-trans-1H-pyrido[4,3-b]indole;and

(±)-8-fluoro-5-(4-fluorophenyl)-2-(6-oxo-1-hexyl)-2,3,4,4a,5,9b-hexahydro-4a,9b-trans-1H-pyrido[4,3-b]indole.

EXAMPLE 41(±)-8-Fluoro-5-(4-fluorophenyl)-2-(5-hydroxyimino-1-pentyl)-2,3,4,4a,5,9b-hexahydro-4a,9b-trans-1H-pyrido[4,3-b]indole

Aminoaldehyde from the preceding Example (370 mg, 1 mmole) is dissolvedin 5 ml of ethanol. Hydroxylamine hydrochloride (69.5 mg, 1 mmole) andsodium bicarbonate (84 mg, 1 mmole) are added and the mixture refluxedfor 16 hours. The reaction mixture is evaporated to dryness and theresidue partitioned between methylene chloride and water. The organicphase is dried and evaporated to yield the title product.

By the same method the other aldehydes of Example 41 are converted to:

(±)-8-fluoro-5-(4-fluorophenyl)-2-(3-hydroxyimino-1-propyl)-2,3,4,4a,5,9b-hexahydro-4a,9b-trans-1H-pyrido[4,3-b]indole;

(±)-8-fluoro-5-(4-fluorophenyl)-2-(4-hydroxyimino-1-butyl)-2,3,4,4a,5,9b-hexahydro-4a,9b-trans-1H-pyrido[4,3-b]indole;and

(±)-8-fluoro-5-(4-fluorophenyl)-2-(6-hydroxyimino-1-hexyl)-2,3,4,4a,5,9b-hexahydro-4a,b9b-trans-1H-pyrido[4,3-b]indole.

Substituting an equivalent of the appropriate substituted hydrazinehydrochloride for hydroxylamine hydrochloride (or substituted hydrazinebase, omitting sodium bicarbonate) the following compounds are prepared:

(±)-8-fluoro-5-(4-fluorophenyl)-2-(5-methylhydrazono-1-pentyl)-2,3,4,4a,5,9b-hexahydro-4a,9b-trans-1H-pyrido[4,3-b]indole;

(±)-8-fluoro-5-(4-fluorophenyl)-2-(5-benzylhydrazono-1-pentyl)-2,3,4,4a,5,9b-hexahydro-4a,9b-trans-1H-pyrido[4,3-b]indole;and

(±)-8-fluoro-5-(4-fluorophenyl)-2-(5-acetylhydrazono-1-pentyl)-2,3,4,4a,5,9b-hexahydro-4a,9b-trans-1H-pyrido[4,3-b]indole.

EXAMPLE 42(±)-8-Fluoro-5-(4-fluorophenyl)-2-(5-hydroxyamino-1-pentyl)-2,3,4,4a,5,9b-hexahydro-4a,9b-trans-1H-pyrido(4,3-b)indole

Oxime from the preceding Example (385 mg, 1 mmole) is combined with 10%aqueous methanol and the pH adjusted to 2-3. Sodium cyanoborohydride(189 mg, 3 mmoles) is added, and the mixture stirred for 4 hours at roomtemperature, maintaining the the pH at 2-3 by addition of dilute mineralacid. The reaction mixture is then allowed to stir for an additional 16hours at room temperature, made basic and extracted with methylenechloride. The extract is dried, filtered and evaporated to yield thetitle product.

By the same method, the other oximes and hydrazones of the precedingExample are converted to:

(±)-8-fluoro-5-(4-fluorophenyl)-2-(3-hydroxyamino-1-propyl)-2,3,4,4a,5,9b-hexahydro-4a,9b-trans-1H-pyrido-[4,3-b]indole;

(±)-8-fluoro-5-(4-fluorophenyl)-2-(4-hydroxyamino-1-butyl)-2,3,4,4a,5,9b-hexahydro-4a,9b-trans-1H-pyrido-[4,3-b]indole;

(±)-8-fluoro-5-(4-fluorophenyl)-2-(6-hydroxyamino-1-hexyl)-2,3,4,4a,5,9b-hexahydro-4a,9b-trans-1H-pyrido-[4,3-b]indole;

(±)-8-fluoro-5-(4-fluorophenyl)-2-[5-(2-methylhydrazino)-1-pentyl]-2,3,4,4a-5,9b-hexahydro-4a,9b-trans-1H-pyrido[4,3-b]indole;

(±)-8-fluoro-5-(4-fluorophenyl)-2-[5-(2-benzylhydrazino)-1-pentyl]-2,3,4,4a,5,9b-hexahydro-4a,9b-trans-1H-pyrido[4,3-b]indole;and

(±)-8-fluoro-5-(4-fluorophenyl)-2-[5-(2-acetylhydrazino)-1-pentyl]-2,3,4,4a,5,9b-hexahydro-4a,9b-trans-1H-pyrido[4,3-b]indole.

EXAMPLE 43(±)-8-Fluoro-5-(4-fluorophenyl-2-[5-(1,2,4-oxadiazolidine-3,5-dion-2-yl)-1-pentyl]-2,3,4,4a,5,9b-hexahydro-4a,9b-trans-1H-pyrido[4,3-b]indole

Hydroxyamino compound of the preceding Example (387 mg, 1 mmole) iscombined with 7.5 ml of chloroform and cooled to 0°-5° C. Triethylamine(222 mg, 2.2 mmole) is added followed by the dropwise addition ofchlorocarbonyl isocyanate (116 mg, 1.1 mmole) in 3 ml of chloroform,keeping the temperature 0°-10° C. The reaction mixture is allowed towarm to room temperature, stirred for an additional 3 hours, and dilutedwith dilute aqueous sodium hydroxide. The organic layer is discarded andthe aqueous layer adjusted to isoelectric pH to precipitate the titleproduct. Alternatively, the aqueous layer is acidified with dilutehydrochloric acid and the title product extracted into 1-butanol as thehydrochloride salt. The latter is isolated by evaporating the driedbutanol layer to dryness.

By the same method the other hydroxyamino and hydrazino compounds of thepreceding Example are converted to:

(±)-8-fluoro-5-(4-fluorophenyl)-2-[3-(1,2,4-oxadiazolidine-3,5-dion-2-yl)-1-propyl]-2,3,4,4a,5,9b-hexahydro-4a,9b-trans-1H-pyrido[4,3-b]indole;

(±)-8-fluoro-5-(4-fluorophenyl)-2-[4-(1,2,4-oxadiazolidine-3,5-dion-1-yl)-1-butyl]-2,3,4,4a,5,9b-hexahydro-4a,9b-trans-1-pyrido[4,3-b]indole;

(±)-8-fluoro-5-(4-fluorophenyl)-2-[6-(1,2,4-oxadiazolidine-3,5-dion-2-yl)-1-hexyl]-2,3,4,4a,5,9b-hexahydro-4a,9b-trans-1H-pyrido[4,3-b]indole;

(±)-8-fluoro-5-(4-fluorophenyl)-2-[5-(1-methyl-1,2,4-triazolidine-3,5-dion-2-yl)-1-pentyl]-2,3,4,4a,5,9b-hexahydro-4a,9b-trans-1H-pyrido[4,3-b]indole;

(±)-8-fluoro-5-(4-fluorophenyl)-2-[5-(1-benzyl-1,2,4-triazolidine-3,5-dion-2-yl)-1-pentyl]-2,3,4,4a,5,9b-hexahydro-4a,9b-trans-1H-pyrido[4,3-b]indole;and

(±)-8-fluoro-5-(4-fluorophenyl)-2-[5-(1-acetyl-1,2,4-triazolidine-3,5-dion-2-yl)-1-pentyl]-2,3,4,4a,5,9b-hexahydro-4a,9b-trans-1H-pyrido[4,3-b]indole.

EXAMPLE 44 3-Benzyl-2,4-imidazolidinedione

Hydantoin (2,4-imidazolidinedione; 25 g, 0.25 mole) was dissolved in 1liter of 90% ethanol. Potassium hydroxide (15 g, 0.27 mole) in 125 ml ofethanol was added and the mixture stirred for 16 hours. The potassiumsalt was recovered by filtration and dried at 80° C. at reduced pressure[25.2 g, m.p. 271°-2° C. (dec)].

Potassium salt (5.5 g, 0.04 mole) and benzyl bromide (17.1 g, 11.9 ml,0.10 mole) were combined with 40 ml of dimethylformamide and the mixturestirred for 16 hours at room temperature and then refluxed for 4 hours.The cooled reaction mixture was filtered and the filtrate evaporated toan oil. The oil was dissolved in chloroform. The chloroform solution waswashed with water and then with saturated brine, dried over anhydrousmagnesium sulfate, filtered and evaporated to solids. Trituration of thesolids with ether gave the title product (3.0 g, m.p. 139°-140° C., m/e190).

By the same method, but generating a sodium salt in situ by the use ofone equivalent of sodium hydride, uracil and dihydrouracil are convertedto 3-benzyl-2,3(1H,3H)-pyrimidinedione and3-benzyl-5,6-dihydro-2,3(1H,3H)-pyrimidinedione.

EXAMPLE 45 3-Benzyl-1-(4-bromo-1-butyl)-2,4-imidazolidinedione

Benzylimidazoline of the preceding Example (1.9 g, 10 mmoles) in 5 ml ofdimethylformamide was added dropwise to a slurry of sodium hydride (528mg of 50% dispersion in oil, 11 mmoles) and the mixture then stirred for1 hour at room temperature. The resulting solution was added dropwise to1,4-dibromobutane (2.37 g, 11 mmole) in 10 ml of dimethylformamide.After stirring 16 hours at room temperature, the reaction mixture waspoured into ice and water and extracted with ethyl acetate. The organiclayer was washed with saturated brine, dried over anhydrous magnesiumsulfate, filtered and evaporated to an oil. The oil was chromatographedon silica gel with chloroform as eluant. Clean product fractions werecombined and evaporated to yield the title product as an oil [1.4 g,pnmr (CDCl₃) delta 1.6-2.0 (m, 4H), 3.2-3.6 (m, 4H), 3.8 (s,2H), 4.6 (s,2H), 7.2-7.5 (m, 5H)].

By the same method, preferably with a larger excess of the appropriatedihaloalkane, the following compounds are prepared:

3-benzyl-1-(3-bromo-1-propyl)-2,4-imidazolidinedione;

3-benzyl-1-(4-chloro-1-butyl)-2,4-imidazolidinedione;

3-benzyl-1-(5-bromo-1-pentyl)-2,4-imidazolidinedione;

and

3-benzyl-1-(6-bromo-1-hexyl)-2,4-imidazolidinedione.

By the same method, preferably with a larger excess of1,4-dibromobutane, the other benzyl-substituted heterocycles of thepreceding Example are converted to:

3-benzyl-1-(4-bromo-1-butyl)-2,3(1H,3H)-pyrimidinedione; and

3-benzyl-1-(4-bromo-1-butyl)-5,6-dihydro-2,3(1H,3H)-pyrimidinedione.

EXAMPLE 46(±)-8-Fluoro-5-(4-fluorophenyl)-2-[4-(3-benzyl-2,4-imidazolidinedion-1-yl)-1-butyl]-2,3,4,4a,5,9b-hexahydro-4a,9b-trans-1H-pyrido[4,3-b]indoleHydrochloride

(±)-8-fluoro-5-(4-fluorophenyl)-2,3,4,4a,5,9b-hexahydro-4a,9b-trans-1H-pyrido[4,3-b]indole(573 mg, 2 mmoles), bromobutylimidazolidinedione of the precedingExample (1.3 g, 4 mmoles), potassium carbonate (1.3 g, 10 mmoles) andpotassium iodide (10 mg) were combined with 4-methyl-2-pentanone (25ml). The mixture was stirred for 4 days at room temperature and thenevaporated to an oil. The oil was dissolved in chloroform, washed withsaturated brine, dried over anhydrous magnesium sulfate, filtered andreevaporated to a second oil. The second oil was chromatographed on 150ml silica gel. A less polar byproduct was removed by elution withchloroform. Product was then eluted from the column with 99:1chloroform:methanol. Clean product fractions were combined andevaporated to yield the free base form (880 mg). The free base wasdissolved in ether and precipitated as a hygroscopic hydrochloride salt(560 mg) by the addition of ethereal hydrogen chloride.Recrystallization from ethyl acetate and then from chloroform/ethylacetate gave the title product in non-hygroscopic form [250 mg, m.p.191°-194° C. (dec)].

Analysis: Calcd. for C₃₁ H₃₂ N₄ O₂ F₂.HCl: C, 65.66; H, 5.86; N, 9.88.Found: C, 65.34; H, 5.73; N, 10.09.

The corresponding chloro compound is substituted for the bromo compoundto yield the same product.

By the same method, the other haloalkylheterocyclic compounds of thepreceding Example are converted to:

(±)-8-fluoro-5-(4-fluorophenyl)-2-[3-(3-benzyl-2,4-imidazolidinedione-1-yl)-1-propyl]-2,3,4,4a,5,9b-hexahydro-4a,9b-trans-1H-pyrido[4,3-b]indole;

(±)-8-fluoro-5-(4-fluorophenyl)-2-[5-(3-benzyl-2,4-imidazolidinedione-1-yl)-1-pentyl]-2,3,4,4a,5,9b-hexahydro-4a,9b-trans-1H-pyrido[4,3-b]indole;

(±)-8-fluoro-5-(4-fluorophenyl)-2-[6-(3-benzyl-2,4-imidazolidinedione-1-yl)-1-hexyl]-2,3,4,4a,5,9b-hexahydro-4a,9b-trans-1H-pyrido[4,3-b]indole;

(±)-8-fluoro-5-(4-fluorophenyl)-2-[[4-[3-benzyl-2,3(1H,3H)-pyrimidinedion-1-yl]-1-butyl]]-2,3,4,4a,5,9b-hexahydro-4a,9b-trans-1H-pyrido[4,3-b]indole;and

(±)-8-fluoro-5-(4-fluorophenyl)-2-[[4-[3-benzyl-5,6-dihydro-2,3(1H,3H)-pyrimidinedion-1-yl]-1-butyl]]-2,3,4,4a,5,9-b-hexahydro-4a,9b-trans-1H-pyrido[4,3-b]indole.

EXAMPLE 47(±)-8-Fluoro-5-(4-fluorophenyl)-2-[4-(2,4-imidazolidinedion-1-yl)-1-butyl]-2,3,4,4a,5,9b-hexahydro-4a,9b-trans-1H-pyrido[4,3-b]indole

By the method of Example 4, the title compound of the preceding Exampleis debenzylated to yield the title compound of the present Example.

By the same method the other benzyl derivatives of the preceding Exampleare debenzylated to yield:

(±)-8-fluoro-5-(4-fluorophenyl)-2-[3-(2,4-imidazolidinedion-1-yl)-1-propyl]-2,3,4,4a,5,9b-hexahydro-4a,9b-trans-1H-pyrido[4,3-b]indole;

(±)-8-fluoro-5-(4-fluorophenyl)-2-[5-(2,4-imidazolidinedion-1-yl)-1-pentyl]-2,3,4,4a,5,9b-hexahydro-4a,9b-trans-1H-pyrido[4,3-b]indole;

(±)-8-fluoro-5-(4-fluorophenyl)-2-[6-(2,4-imidazolidinedion-1-yl)-hexyl]-2,3,4,4a,5,9b-hexahydro-4a,9b-trans-1H-pyrido[4,3-b]indole;

(±)-8-fluoro-5-(4-fluorophenyl)-2-[[4-[2,3(1H,3H)-pyrimidinedion-1-yl]-butyl]]-2,3,4,4a,5,9b-hexahydro-4a,9b-trans-1H-pyrido[4,3-b]indole;and

(±)-8-fluoro-5-(4-fluorophenyl)-2-[[4-[5,6-dihydro-2,3(1H,3H)-pyrimidinedion-1-yl]-butyl]]-2,3,4,4a,5,9b-hexahydro-4a,9b-trans-1H-pyrido[4,3-b]indole.

EXAMPLE 48 1-(4-Bromo-1-butyl)-1,2,3,6-tetrahydro-3,6-pyridazinedione

By the method of Example 1, 3,6-dihydroxypyridazine is reacted with1,4-dibromobutane to yield the title product.

By the same method phthalhydrazide, succinhydrazide, malonhydrazide and2,4-pyrrolidindione are converted, respectively, to2-(4-bromo-1-butyl)-1,2,3,4-tetrahydro-1,4-benzo[c]pyridazinedione,1-(4-bromo-1-butyl)-hexahydro-3,6-pyridazinedione,1-(4-bromo-1-butyl)-3,5-pyrazolidinedione and1-(4-bromo-1-butyl)-2,4-pyrrolidinedione.

EXAMPLE 49(±)-8-Fluoro-5-(4-fluorophenyl)-2-[4-(1,2,3,6-tetrahydropyridazine-3,6-dion-1-yl)-1-butyl]-2,3,4,4a,5,9b-hexahydro-4a,9b-trans-1H-pyrido[4,3-b]indole

By the method of Example 2, the bromobutyl derivative of the precedingExample is reacted with(±)-8-fluoro-5-(4-fluorophenyl)-2,3,4,4a,5,9b-hexahydro-4a,9b-trans-1H-pyrido[4,3-b]indoleto yield the title product.

In like manner, the other bromobutyl derivatives of the precedingExample are converted to:

(±)-8-fluoro-5-(4-fluorophenyl)-2-[4-(1,2,3,4-tetrahydro-1,4-benzo[c]pyridazinedion-2-yl)-1-butyl]-2,3,4,4a,5,9b-hexahydro-4a,9b-trans-1H-pyrido[4,3-b]indole;

(±)-8-fluoro-5-(4-fluorophenyl)-2-[4-(hexahydro-3,6-pyridazindion-1-yl)-1-butyl]-2,3,4,4a,5,9b-hexahydro-4a,9b-trans-1H-pyrido[4,3-b]indole;

(±)-8-fluoro-5-(4-fluorophenyl)-2-[4-(3,5-pyrazolidindion-1-yl)-1-butyl]-2,3,4,4a,5,9b-hexahydro-4a,9b-trans-1H-pyrido[4,3-b]indole;and

(±)-8-fluoro-5-(4-fluorophenyl)-2-[4-(2,4-pyrrolidinedione-1-yl)-1-butyl]-2,3,4,4a,5,9b-hexahydro-4a,9b-trans-1H-pyrido[4,3-b]indole.

EXAMPLE 50 2-(4-Chloro-1-butyl)-3(2H)-benz[d]isothiazolone 1,1-Dioxide

Sodium saccharin (5.6 g, 0.027 mole) and 1,4-dichlorobutane (14.9 ml,0.135 mole) were taken into 100 ml of dimethylformamide and heated on asteam bath for 4 hours. The reaction mixture was evaporated in vacuo toan oil and the oil extracted with 100 ml of hexane. Residual hexane wasremoved from the remaining oil by vacuum evaporation to yield the titleproduct (956 mg).

EXAMPLE 51(±)-8-Fluoro-5-(4-fluorophenyl-2-[[4-[1,1-dioxo-3(2H)-benz[d]isothiazolon-2-yl]-1-butyl]]-2,3,4,4a,5,9b-trans-1H-pyrido[4,3-b]indoleHydrochloride

The title compound of the preceding Example (956 mg, 3.5 mmoles),(±)-8-fluoro-5-(4-fluorophenyl)-2,3,4,4a,5,9b-hexahydro-4a,9b-trans-1-H-pyrido[4,3-b]indole(500 mg, 1.75 mmoles), anhydrous sodium carbonate (1.1 g, 10.5 mmoles)and potassium iodide (5 mg) were reacted in 3-methyl-2-butanone (20 ml)by the method of Example 2. Following the 16 hour reflux period, thereaction mixture was evaporated to gum and the gum chromatographed onsilica gel with 1:1 methylene chloride:ethyl acetate as eluant. Thecolumn was monitored by tlc; single component product fractions werecombined and evaporated to a second gum. The second gum was dissolved inether, acidified with ethereal hydrogen chloride and the resultingsuspension evaporated to yield the title product [339 mg; Rf 0.45 (1:1methylene chloride:ethyl acetate)].

Analysis: Calcd. for C₂₈ H₂₇ N₃ O₃ SF₂.HCl.H₂ O: C, 58.18; H, 5.23; N,7.26. Found: C, 57.90; H, 5.21; N, 7.07.

EXAMPLE 52(±)-8-Fluoro-5-(4-fluorophenyl)-2-[4-(2,3-dihydro-2,3(1H)-isoindoledione-2-yl)-1-butyl]-2,3,4,4a,5,9b-hexahydro-4a,9b-trans-1H-pyrido[4,3-b]indoleHydrochloride

By the procedure of Example 2, N-(4-bromo-1-butyl)-phthalimide (0.985 g,3.5 mmoles) was converted to the title product. The crude productisolated from the water/methylene chloride partition was chromatographedon silica gel with 1:1 ethyl acetate:methylene chloride as eluant andtlc monitoring. Clean product fractions were combined and evaporated toa gum. The gum was dissolved in ether and converted to hydrochloridesalt by the addition of ethereal hydrogen chloride. The resultingsuspension was taken to dryness and the residue crystallized fromacetone to yield the title product [425 mg, m.p. 169°-171° C., Rf 0.55(1:1 ethyl acetate:methylene chloride)].

Analysis: Calcd. for C₂₉ H₂₇ N₃ O₂ F₂.HCl.H₂ O: C, 64.26; H, 5.57; N,7.75. Found: C, 64.01; H, 5.14; N, 7.64.

By the same method N-(4-bromo-1-butyl)succinimide,N-(4-bromo-1-butyl)glutarimide and N-(4-bromo-1-butyl)-maleimide areconverted, respectively, to:

(±)-8-fluoro-5-(4-fluorophenyl)-2-[4-(2,5-pyrrolidinedion-1-yl)-1-butyl]-2,3,4,4a,5,9b-hexahydro-4a,9b-trans-1H-pyrido[4,3-b]indole;

(±)-8-fluoro-5-(4-fluorophenyl)-2-[4-(2,6-piperidinedione-1-yl)-1-butyl]-2,3,4,4a,5,9b-hexahydro-4a,9b-trans-1H-pyrido[4,3-b]indole;and

(±)-8-fluoro-5-(4-fluorophenyl)-2-[4-(3-pyrroline-2,5-dion-1-yl)-1-butyl]-2,3,4,4a,5,9b-hexahydro-4a,9b-trans-1H-pyrido[4,3-b]indole.

EXAMPLE 53 3-(4-Chloro-1-butyl)-2,4-thiazolidinedione

By the procedure of Example 1, 2,4-thiazolidinedione (8 g, 0.068 mole)was converted to the title product. The reaction mixture was filteredand evaporated to an oil. The oil was triturated with methylenechloride, solids removed by filtration and the filtrate reevaporated toyield the desired product as an oil [Rf 0.2 (4:1 ethylacetate:methanol)].

By the same procedure 3,4,5,6-tetrahydro-1,3(2H)-thiazine-2,4-dione isconverted to3-(4-chloro-1-butyl)-3,4,5,6-tetrahydro-1,3(2H)-thiazine-2,4-dione.

EXAMPLE 54(±)-8-Fluoro-5-(4-fluorophenyl)-2-[4-(2,4-thiazolidinedione-3-yl)-1-butyl]-2,3,4,4a,5,9b-hexahydro-4a,9b-trans-1H-pyrido[4,3-b]indoleHydrochloride

By the procedure of Example 2, the chlorobutylthiazolidine of thepreceding Example (543 mg, 2.62 mmole) was converted to the crude freebase form of the title compound.

The crude base was chromatographed on silica gel with ethanol as eluantand tlc monitoring. Clean product fractions were combined and evaporatedto a gum. The gum was dissolved in ether and acidified with etherealhydrogen chloride. Evaporation to solids and reslurry in hexane gave thetitle product (479 mg, hygroscopic).

Analysis: Calcd. for C₂₄ H₂₅ F₂ O₂ N₃ S.HCl.1.2 H₂ O: C, 55.90; H, 5.51;N, 8.15. Found: C, 55.57; H, 4.96; N, 8.01.

By the same procedure the chlorobutylthiazine of the preceding Exampleis converted to:

(±)-8-fluoro-5-(4-fluorophenyl)-2-[4-(3,4,5,6-tetrahydro-1,3(2H)-thiazine-2,4-dion-3-yl)-1-butyl]-2,3,4,4a,5,9b-hexahydro-4a,9b-trans-1H-pyrido[4,3-b]indole.

EXAMPLE 55(±)-8-Fluoro-5-(4-fluorophenyl)-2-[2-(2,4-imidazolidinedion-3-yl)ethyl]-2,3,4,4a,5,9b-hexahydro-4a,9b-trans-1H-pyrido[4,3-b]indole

By the procedure of Example 2,(±)-8-fluoro-5-(4-fluorophenyl)-2,3,4,4a,5,9b-hexahydro-4a,9b-trans-1H-pyrido[4,3-b]indole(573 mg, 2 mmoles) was reacted with3-(2-bromoethyl)-2,4-imidazolidinedione (828 mg, 4 mmoles) to form thetitle product. The reaction mixture was filtered with chloroform wash,and the combined filtrate and washings evaporated to dryness. The solidresidue was chromatographed on 100 ml of silica gel with ethyl acetateas eluant and tlc monitoring. Clean product fractions were combined,evaporated to dryness, and the residue recrystallized fromchloroform/hexane to yield the title product [444 mg, m.p. 195°-197° C.(dec)]. For analysis, 200 mg was further recrystallized from methanol[180 mg, m.p. 191°-193° C. (dec)].

Analysis: Calcd. for C₂₂ H₂₂ F₂ N₄ O₂ : C, 64.07; H, 5.38; N, 13.58.Found: C, 63.72; H, 5.47; N, 13.45.

EXAMPLE 56 3-(3-Bromo-1-propyl)-2,4-imidazolidindione

The potassium salt of 2,4-imidazolinedione (hydantoin; 5.5 g, 0.04 mole;prepared as in Example 44) was reacted with 1,3-dibromopropane (14.3 ml,0.14 mole) in 50 ml of dimethylformamide for 16 hours at roomtemperature and then for 2 hours at reflux. The reaction mixture wasfiltered, evaporated to dryness, and the residue recrystallized fromisopropyl alcohol (950 mg, m.p. 103°-106° C., m/e 222/220).

EXAMPLE 57(±)-8-Fluoro-5-(4-fluorophenyl)-2-[3-(2,4-imidazolidinedion-3-yl)-1-propyl]-2,3,4,4a,5,9b-hexahydro-4a,9b-trans-1H-pyrido[4,3-b]indoleMethanesulfonate

(±)-8-fluoro-5-(4-fluorophenyl)-2,3,4,4a,5,9b-hexahydro-4a,9b-trans-1H-pyrido[4,3-b]indole(573 mg, 2 mmoles) and 3-(3-bromo-1-propyl)-2,4-imidazolidindione (884mg, 4 mmoles), sodium carbonate (1.06 g, 10 mmoles), potassium iodide(10 mg) and 10 ml of 4-methyl-2-pentanone were combined and the mixtureheated at 80°-90° C. for 5 hours. At this time tlc monitoring (9:1chloroform:methanol) indicated complete consumption of the pyridoindolestarting material. The reaction mixture was filtered and the filtrateevaporated to dryness. The residue was dissolved in ethanol and etheradded to the cloud point, allowed to stand for 16 hours, filtered andthe filtrate evaporated to dryness to yield the free base form of thetitle product (900 mg). Free base was dissolved in ethanol. Twoequivalents of methanesulfonic acid were added. The title product(mesylate salt) crystallized on standing and was recovered by filtration[530 mg, m.p. 246°- 249° C. (dec); m/e 426].

Analysis: Calcd. for C₂₃ H₂₄ N₄ O₂ F₂.CH₄ SO₃.0.33 H₂ O: C, 54.54; H,5.47; N, 10.60. Found: C, 54.48; H, 5.33; N, 10.66.

EXAMPLE 58 3-(6-Bromo-1-hexyl)-2,4-imidazolidinedione

By the procedure of Example 56, 1,6-dibromohexane (24.2 g, 0.10 mole)was reacted to form title product. The reaction mixture was filtered,the filtrate evaporated to an oil and the oil dissolved in chloroform.The chloroform solution was washed with water and then saturated brine,dried over anhydrous magnesium sulfate, filtered and evaporated to asecond oil, which crystallized from ether/hexane (3.7 g, m.p. 84°-86°C., m/e 264/262).

By the same procedure2,4-dihydroxypyrimidine[2,4(1H,3H)-pyrimidinedione] and5,6-dihydrouracil (hexahydro-2,4-pyrimidinedione) are converted to3-(6-bromo-1-hexyl)-2,4(1H,3H)pyrimidinedione and3-(6-bromo-1-hexyl)hexahydro-2,4-pyrimidinedione.

EXAMPLE 59(±)-8-Fluoro-5-(4-fluorophenyl)-2-[6-(2,4-imidazolidinedion-3-yl)-1-hexyl]-2,3,4,4a,5,9b-hexahydro-1H-pyrido[4,3-b]indoleHydrochloride

By the procedure of Example 55,3-(6-bromo-1-hexyl)-2,4-imidazolidinedione (1.05 g, 0.04 moles) wasreacted to form the title product, except that the eluant onchromatography was 19:1 chloroform:methanol. The free base was isolatedas an oil from the clean column fractions. The base was dissolved inethanol and ethanolic hydrogen chloride added to precipitate thehydrochloride. Two recrystallizations from ethanol gave the titleproduct in purified form (220 mg, m.p. 168°-171° C.).

Analysis: Calcd. for C₂₆ H₃₀ F₂ N₄ O₂.HCl.0.5 H₂ O: C, 60.75; H, 6.28;N, 10.90. Found: C, 60.47; H, 5.90; N, 10.82.

By the same method, the other 6-bromohexyl derivatives of the precedingExample are converted to:

(±)-8-fluoro-5-(4-fluorophenyl)-2-[6-(2,4(1H,3H)-pyrimidindion-3-yl)-1-hexyl]-2,3,4,4a,5,9b-hexahydro-4a,9b-trans-1H-pyrido[4,3-b]indole;and

(±)-8-fluoro-5-(4-fluorophenyl)-2-[6-(hexahydro-2,4-pyrimidinedion-3-yl)-1-hexyl]-2,3,4,4a,5,9b-hexahydro-4a,9b-trans-1H-pyrido[4,3-b]indole.

EXAMPLE 608-Fluoro-5-(4-fluorophenyl)-2-[4-(2-piperidon-1-yl)-1-butyl]-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indoleHydrochloride

By the method of Example 2,8-fluoro-5-(4-fluorophenyl)-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole (2g, 7.0 mmoles) was reacted with 1-(4-chloro-1-butyl)-2-piperidone (1.98g, 10.5 mmoles) to yield crude free base, a gum. The crude base waschromatographed on silica gel, with ethyl acetate as eluant. Cleanproduct fractions were evaporated to dryness, taken up in acetone andthe title product precipitated by the addition of ethereal hydrogenchloride (1.2 g, m.p. 202°-205° C.).

Analysis: Calcd. for C₂₆ H₂₉ F₂ N₃ O.HCl.0.5 H₂ O: C, 64.65; H, 6.21; N,8.70. Found: C, 64.75; H, 6.37; N, 8.58.

By the same method the other haloalkylpiperidones of Examples 1 and 6are converted to:

8-fluoro-5-(4-fluorophenyl)-2-[2-(2-piperidon-1-yl)-ethyl]-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole;

8-fluoro-5-(4-fluorophenyl)-2-[3-(2-piperidon-1-yl)-1-propyl]-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole;

8-fluoro-5-(4-fluorophenyl)-2-[5-(2-piperidon-1-yl)-1-pentyl]-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole;

8-fluoro-5-(4-fluorophenyl)-2-[6-(2-piperidon-1-yl)-1-hexyl]-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole;

8-fluoro-5-(4-fluorophenyl)-2-[7-(2-piperidon-1-yl)-1-heptyl]-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole;

8-fluoro-5-(4-fluorophenyl)-2-[8-(2-piperidon-1-yl)-1-octyl]-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole;and

8-fluoro-5-(4-fluorophenyl)-2-[9-(2-piperidon-1-yl)-1-nonyl]-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole.

By the same method, substituting 1-(4-chloro-1-butyl)-2-piperidone with1-(4-chloro-1-butyl)-2-pyrrolidinone,N-(4-chloro-1-butyl)-6-hexanelactam, the following compounds areprepared:

8-fluoro-5-(4-fluorophenyl)-2-[4-(2-pyrrolidinon-1-yl)-1-butyl]-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole;and

8-fluoro-5-(4-fluorophenyl)-2-[4-(2-perhydroazepinon-1-yl)-1-butyl]-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole.

By the same method the appropriately substituted5-phenyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indoles are converted to:

5-phenyl-2-[4-(2-piperidon-1-yl)-1-butyl]-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole;

8-fluoro-5-(2-fluorophenyl)-2-[4-(2-piperidon-1-yl)-1-butyl]-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole;

8-fluoro-5-(3-chlorophenyl)-2-[4-(2-piperidon-1-yl)-1-butyl]-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole;

8-fluoro-5-(4-ethylphenyl)-2-[4-(2-piperidon-1-yl)-1-butyl]-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole;

8-fluoro-5-(4-fluoro-2-methyl)-2-[4-(2-piperidon-1-yl)-1-butyl]-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole;

8-chloro-5-(4-chlorophenyl)-2-[4-(2-piperidon-1-yl)-1-butyl]-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole;

8-ethyl-5-(4-ethylphenyl)-2-[4-(2-piperidon-1-yl)-1-butyl]-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole;and

8-methoxy-5-(4-methoxyphenyl)-2-[4-(2-piperidon-1-yl)-1-butyl]-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole.

EXAMPLE 618-Fluoro-5-(4-fluorophenyl)-2-(5-cyano-1-pentyl)-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole

8-fluoro-5-(4-fluorophenyl)-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole(10.8 g, 0.034 mole), 6-bromohexanenitrile (6.5 g, 0.037 mole),anhydrous sodium carbonate (21.6 g, 0.204 mole), potassium iodide (100mg) and 3-methyl-2-butanone (250 ml) were combined and the mixturerefluxed for 24 hours. The reaction mixture was cooled, diluted with 250ml of water and stirred to dissolve excess sodium carbonate. The layerswere separated and the aqueous layer extracted with 200 ml of methylenechloride. The organic layers were combined, dried over anhydrousmagnesium sulfate, filtered and evaporated to an oil. Addition of hexanegave the title product in crystalline form [11.3 g, m.p. 90°-98° C., Rf0.5 (9:1 ethyl acetate:methanol)].

By the same method, 2-bromoethanenitrile, 3-bromopropanenitrile,4-bromobutanenitrile, 5-bromopentanenitrile, 7-bromoheptanenitrile and8-bromooctanenitrile are converted, respectively, to:

8-fluoro-5-(4-fluorophenyl)-2-cyanomethyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole;

8-fluoro-5-(4-fluorophenyl)-2-(2-cyano-1-ethyl)-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole;

8-fluoro-5-(4-fluorophenyl)-2-(3-cyano-1-propyl)-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole;

8-fluoro-5-(4-fluorophenyl)-2-(4-cyano-1-butyl)-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole;

8-fluoro-5-(4-fluorophenyl)-2-(6-cyano-1-hexyl)-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole;and

8-fluoro-5-(4-fluorophenyl)-2-(7-cyano-1-heptyl)-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole.

EXAMPLE 628-Fluoro-5-(4-fluorophenyl)-2-(6-amino-1-hexyl)-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole

At room temperature, the title compound of the preceding Example (11.3g, 0.03 moles) was stirred in 500 ml of ether for 15 minutes, by whichtime almost complete solution had resulted. Lithium aluminum hydride(3.0 g) was added in portions with vigorous stirring. After stirring foran additional 1.5 hours, about 5 g of Glauber's salt was added in five 1g portions and stirring continued for 15 minutes. Solids were removed byfiltration with tetrahydrofuran wash. The combined filtrate and wash wasevaporated to yield the title product as an oil [10.7 g; Rf 0.1 (9:1ethyl acetate:methanol), 0.1 (9:1 methanol:acetic acid)].

By the same method, the other nitriles of the preceding Example areconverted to:

8-fluoro-5-(4-fluorophenyl)-2-(2-aminoethyl)-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole;

8-fluoro-5-(4-fluorophenyl)-2-(3-amino-1-propyl)-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole;

8-fluoro-5-(4-fluorophenyl)-2-(4-amino-1-butyl)-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole;

8-fluoro-5-(4-fluorophenyl)-2-(5-amino-1-pentyl)-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole;

8-fluoro-5-(4-fluorophenyl)-2-(7-amino-1-heptyl)-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole;and

8-fluoro-5-(4-fluorophenyl)-2-(8-amino-1-octyl)-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole.

EXAMPLE 638-Fluoro-5-(4-fluorophenyl)-2-(6-acetamido-1-hexyl)-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole

At room temperature, the title amino compound of the preceding Example(10.7 g, 0.028 mole) was dissolved in 80 ml of methylene chloride.Triethylamine (15.6 ml, 0.112 mole) was added and then, in a dropwisemanner, acetyl chloride (2.35 g, 0.030 mole) in 20 ml of methylenechloride. A mild exotherm was noted. The mixture was stirred for 30minutes more, then concentrated to an oil (14 g). The oil waschromatographed on silica gel with 1:1 methanol:ethyl acetate as eluantand tlc monitoring. Clean product fractions were combined, evaporated todryness and the residue crystallized from ether to yield the titleproduct in purified form [6.33 g; m.p. 114°-116° C.; Rf 0.6 (1:1methanol:ethyl acetate)].

Analysis: Calcd. for C₂₅ H₂₉ ON₃ F₂ : C, 70.56; H, 6.87; N, 9.88. Found:C, 70.34; H, 6.96; N, 9.66.

By the same method, the other amino compounds of the preceding Examplewere converted to:

8-fluoro-5-(4-fluorophenyl)-2-(2-acetamidoethyl)-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole;

8-fluoro-5-(4-fluorophenyl)-2-(3-acetamido-1-propyl)-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole;

8-fluoro-5-(4-fluorophenyl)-2-(4-acetamido-1-butyl)-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole;

8-fluoro-5-(4-fluorophenyl)-2-(5-acetamido-1-pentyl)-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole;

8-fluoro-5-(4-fluorophenyl)-2-(7-acetamido-1-heptyl)-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole;and

8-fluoro-5-(4-fluorophenyl)-2-(8-acetamido-1-octyl)-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole.

By the same method, substituting the appropriate anhydride or acidchloride for acetyl chloride [specifically acetoformic acid reagent, cf.Blackwood et al., J. Am. Chem. Soc. 82, pp. 5194-5197 (1960), in thecase of the formyl derivative], the following compounds are prepared:

8-fluoro-5-(4-fluorophenyl)-2-(6-formamido-1-hexyl)-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole;

8-fluoro-5-(4-fluorophenyl)-2-(6-isobutyrylamino-1-hexyl)-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole;

8-fluoro-5-(4-fluorophenyl)-2-(6-isovalerylamino-1-hexyl)-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole;and

8-fluoro-5-(4-fluorophenyl)-2-(6-heptanoylamino-1-hexyl)-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole.

EXAMPLE 648-Fluoro-5-(4-fluorophenyl)-2-(6-ethoxycarbonylamino-1-hexyl)-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole

Following the procedure of the preceding Example,8-fluoro-5-(4-fluorophenyl)-2-(6-amino-1-hexyl)-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole(1.6 g, 4.2 mmoles) was reacted with ethylchloroformate (0.45 ml, 4.6moles) in methylene chloride (5 ml) in the presence of triethylamine(2.3 ml, 16.7 mmoles), and the title product isolated and purified,except that ethyl acetate was used as eluant in the silica gelchromatography (365 mg, m.p. 159°-162° C.).

Analysis: Calcd. for C₂₆ H₃₁ O₂ N₃ F₂.HCl.0.75 H₂ O: C, 61.77; H, 6.33;N, 8.31. Found: C, 61.84; H, 6.47; N, 8.33.

By the same method, substituting the appropriate alkyl chloroformate forethyl chloroformate, the following compounds are prepared:

8-fluoro-5-(4-fluorophenyl)-2-(6-methoxycarbonylamino-1-hexyl)-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole;

8-fluoro-5-(4-fluorophenyl)-2-(6-isopropoxycarbonylamino-1-hexyl)-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]-indole;and

8-fluoro-5-(4-fluorophenyl)-2-(1-hexyloxycarbonylamino-1-hexyl)-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole.

We claim:
 1. A tetrahydro-1H-pyridoindole derivative of the formula##STR49## or a pharmaceutically acceptable salt thereof, wherein k is 1or 2;n is 2 to 9; X and Y are independently H, F, Cl, Br, OCH₃, CH₃ orCH₂ CH₃ ; R⁵ taken separately is hydrogen; R⁶ taken separately is (C₁-C₈)alkanoyl or (C₁ -C₇)alkoxycarbonyl; and R⁵ and R⁶ taken together are##STR50## wherein r is 3 to
 5. 2. A derivative of claim 1 wherein k is1, X is F and Y is para-F.
 3. A derivative of claim 2 wherein n is 3 to6.
 4. A derivative of claim 3 wherein R⁵ and R⁶ are taken separately andR⁶ is acetyl or carbethoxy.
 5. The derivative of claim 4 wherein n is 6and R⁶ is acetyl.
 6. The derivative of claim 4 wherein n is 6 and R⁶ iscarbethoxy.
 7. A derivative of claim 3 wherein R⁵ and R⁶ are takentogether and are ##STR51##
 8. The derivative of claim 7 wherein n is 4.9. The derivative of claim 7 wherein n is
 6. 10. A method of treatingpsychoses and neuroses in a patient requiring major tranquilizationwhich comprises administering to the patient by oral, intravenous,intramuscular or subcutaneous route an effective amount of a compound ofclaim 1.